|Year : 2019 | Volume
| Issue : 1 | Page : 1-9
Cholesterol-mediated regulation of angiogenesis: An emerging paradigm
Lingping Zhu1, Qilin Gu2, Longhou Fang2
1 Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas, USA; Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China
2 Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas, USA
|Date of Web Publication||28-Mar-2019|
Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030
Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030
Source of Support: None, Conflict of Interest: None
Angiogenesis, the fundamental process that generates new blood vessels from parental vessels, is essential for embryogenesis and pathogenesis. A variety of underlying molecular and cellular mechanisms control angiogenesis. In this review, we focus on a unique mechanism of action – cholesterol-regulated angiogenesis. We will discuss lipoproteins, including low-density lipoprotein and high-density lipoprotein, cholesterol-rich lipid rafts/caveolae, apoA-I-binding protein (AIBP, also known as NAXE)-regulated cholesterol efflux, the effect of the hydroxycholesterol-activated nuclear receptor liver X receptor α/β on the proangiogenic vascular endothelial growth factor receptor 2 and antiangiogenic Notch signaling, and cholesterol-modified sonic hedgehog signaling. These pathways can be exploited, either alone or in conjunction with the currently available regimen for angiogenesis treatment, to control neovascularization in dyslipidemia. A treatment protocol for angiogenesis that takes into consideration cholesterol management might constitute an important component in precision and personalized medicine.
Keywords: ApoA-I-binding protein, angiogenesis, cholesterol efflux, notch signaling, pathways, vascular endothelial growth factor receptor 2
|How to cite this article:|
Zhu L, Gu Q, Fang L. Cholesterol-mediated regulation of angiogenesis: An emerging paradigm. Cardiol Plus 2019;4:1-9
| Introduction|| |
In this review, we only focus on cholesterol-mediated regulation of angiogenesis from the aspects of lipid rafts/caveolae, lipoproteins, apoA-I-binding protein (AIBP)-mediated cholesterol efflux, oxysterol-regulated liver X receptor (LXR) transcription factor, and cholesterol-modified sonic hedgehog (Shh). For other mechanisms governing developmental or tumor angiogenesis, please read extensive reviews previously published.,,,,
| Cholesterol Efflux and Cholesterol-Rich Lipid Rafts/Caveolae in Regulation of Angiogenesis|| |
Lipid rafts/caveolae are 50–100-nm size flat microdomains or invaginations that are localized on the plasma membrane. Cholesterol, along with the lipophilic sphingolipid, plays a pivotal role in the organization of lipid rafts/caveolae, and its removal can disrupt the lipid rafts/caveolae structure. Cellular cholesterol removal is carried out by a variety of cholesterol transporters, for example, ATP-binding cassette family member ABCA1 and ABCG. ABCA1 mediates phospholipids and cholesterol efflux to apoA-I,, which transforms into high-density lipoprotein (HDL), while ABCG1 and ABCG4 donate cholesterol to acceptor HDL.,,, Deficiencies in ABCA1, ABCG1, or both increase free cholesterol levels in hematopoietic stem and progenitor cells (HSPC), while ABCG4 depletion increases cholesterol levels in megakaryocytes.,,, Similarly, endothelial cell (EC)-specific knockout of ABCA1 and ABCG1 increases cholesterol content in lung ECs following a high-fat diet. Interestingly, although combined ABCA1 and ABCG1 knockout dramatically diminishes cholesterol efflux to apoA-I, cholesterol efflux to HDL reduces only by approximately 20%, which could be due to the effect of SR-BI or other unknown mechanisms of cholesterol removal. The ex vivo murine aortic ring assay indicates that loss of ABCG1, alone or in concert with ABCA1, strongly augments neovascularization, which is supportive of ABCG1 as the main transporter responsible for cholesterol removal in ECs. However, all these assays were performed in either an in vitro or ex vivo cell culture system, and thus, there is ample external source of HDL from serum. However, in vivo in zebrafish, knockdown of cholesterol transporter A1 causes a more robust angiogenic sprouting compared to ABCG1 knockdown. It is possible that loss of ABCA1 negates the initial process of generating HDL, which results in no HDL acceptor for ABCG1 to function properly, as reported in mice.,,, In this circumstance, loss of ABCA1 in animals causes a situation similar to ABCA1 and ABCG1 combined deficiency. Consistent with this speculation, loss of ABCA1 in human results in significant reduction of HDL-C levels.,, Mechanistically, ABCA1 and ABCG1 affect angiogenesis through their ability to modulate the content of cholesterol-rich lipid rafts, which is critical for vascular endothelial growth factor receptor 2 (VEGFR2) signaling. Lipid rafts facilitate VEGFR2 dimerization following vascular endothelial growth factor-A (VEGFA) stimulation, which is an important step for VEGFR2 phosphorylation and signaling. Endocytosis consists of a critical process of prolonged VEGFR2 activation after VEGFA engagement., However, epsin1/2 deficiency, which impairs VEGFR2 endocytosis, paradoxically enhances VEGFR2 signaling. A compensatory pathway may be activated to shunt the endocytosis step for its activation. Alternatively, endocytosis is a double-edge sword that regulates VEGFR2 signaling, which prolongs VEGFR2 activity in the cytosol but diminishes the level of plasma membrane VEGFR2 that can reinitiate another round of VEGF binding and endocytosis. Without endocytosis, in the case of epsin 1/2 deficiency, VEGFR2 may keep transmitting activation signals.
Cav-1, the major scaffolding protein of caveolae, orchestrates angiogenesis in a context-dependent fashion. Cav-1 knockout eliminates endothelial caveolae in mice., Cav-1 deficiency is reported to disrupt cell surface receptor signaling and impair angiogenesis.,,,, Consistent with these findings, we and others have shown that decreased caveolae abundance by cholesterol removal inhibits VEGFR2 activation and restricts developmental angiogenesis., Cav-1 depletion, on the other hand, exhibits an proangiogenic effect. For example, Cav-1 knockout mice show greater tumor angiogenesis and hyperpermeability., Cav-1 regulates angiogenesis in part through its interaction with eNOS,,, the key enzyme for NO production in ECs. eNOS is localized in lipid rafts/caveolae and is essential for the maintenance of vascular tone and angiogenesis. Treatment with L-NAME, an eNOS inhibitor, impairs angiogenesis, and conversely, supplement with NO donor L-arginine enhances neovessel formation in an eNOS-dependent fashion in the hindlimb ischemia model.,, In addition, VEGFR2 signaling activates eNOS,, and reciprocally, forced eNOS expression increases VEGF expression in the blood vessels. In high fat diet-challenged ABCG1 knockout mice, increased Cav-1 and eNOS interaction impairs eNOS activation and attenuates EC function. ABCG1-mediated cholesterol efflux to HDL can reduce Cav-1 and eNOS interaction, thereby alleviating the inhibitory effect of Cav-1 on eNOS and improving EC function.
Although lipid rafts often facilitate VEGFR2 signaling, lipid raft disruption by cholesterol removal may have enhancement or inhibitory effects on VEGFR2 signaling. There are several reasons that may account for the discrepancies. First, it is important to ensure that the biological consequence of cholesterol content variance is due to cholesterol proper and not because of the contaminant in chemical (e.g., endotoxin)-induced effects. As such, addition of cholesterol back into cholesterol-depleted cells is a critical control. Second, a possible scenario that accommodates this seemingly contradictory effect on angiogenesis is that, as for many biological events, there may exist a threshold of lipid raft content for optimal VEGFR2 signaling, as in the case of cholesterol effect on Notch signaling [Figure 1], below or above the threshold may have an anti-angiogenic effect. The same may hold true for the different observations of angiogenesis made in Cav1-/- animals. Another possibility to consider is Cav1-mediated endocytosis, which accordingly adds another layer of complexity to the lipid rafts/caveolae effect on angiogenesis. In addition, cholesterol demonstrates a pleiotropic effect on the lipid bilayer membrane in an in vitro test tube using reconstitution system. Whether these effects occur in vivo requires future investigation.
|Figure 1: ApoA-I-binding protein promotes cholesterol efflux and regulates Notch signaling. ApoA-I-binding protein-mediated cholesterol efflux reduces lipid raft abundance, which boosts Notch1 signaling by improving their codistribution in nonrafts|
Click here to view
Recombinant apoA-I, or its mimetic peptides, which accepts plasma membrane cholesterol from the lipid raft microdomains, has been applied to target angiogenesis., We show that apoA-I overexpression corrects accelerated retinal angiogenesis in AIBP knockout mice [Figure 2]. Administration of purified human apoA-I also shows diverse effects on neovessel formation depending on the model system. For example, reconstituted HDL (rHDL) restricts inflammatory angiogenesis while it promotes hypoxia-induced angiogenesis by increasing VEGFA/VEGFR2 expression and activation. In the inflammatory milieu of murine perivascular carotid collar model or tumorigenesis, apoA-I appears to limit angiogenesis, whereas apoA-I or rHDL accelerates hypoxia-elicited neovascularization in the murine hindlimb ischemia model. HDL concentration is also a factor of consideration. For example, HDL in the range of 40–80 mg/dL is shown to inhibit in vitro angiogenesis through activation of Rho-associated kinase and inhibition of PI3K/Akt and p38 in endothelial progenitor cells (EPC). HDL receptor SR-BI mediates certain proangiogenic effects of HDL on eNOS activation, cell migration, and in vivo matrigel angiogenesis. In addition, apoA-I also exhibits a stimulatory effect on EC proliferation and angiogenesis through its cell surface receptor F1F0 ATP synthase.
|Figure 2: ApoA-I-binding protein-mediated targeted cholesterol efflux from endothelial cells disrupts lipid rafts/caveolae and suppresses vascular endothelial growth factor receptor 2 signaling. Vascular endothelial growth factor-A-induced vascular endothelial growth factor receptor 2 signaling induces the receptor dimerization in cholesterol-rich caveolae. ApoA-I-binding protein-mediated cholesterol removal disrupts lipid rafts/caveolae, which impairs vascular endothelial growth factor receptor 2 signaling and limits angiogenesis|
Click here to view
| Lipid Raft-Independent Effects of Lipoproteins On Angiogenesis|| |
HDL exhibits pro- or anti-angiogenic effects on angiogenesis that are not associated with its function in lipid raft disruption. In many studies, the primary effect of HDL on angiogenesis ascribes to its association with bioactive lipid – sphingosine-1-phosphate (S1P).,,,, S1P binds apoM, which is present on HDL, and demonstrates distinct biological activities in angiogenesis and vascular integrity. Shear stress augments S1P bioavailability by reducing S1P lyase that decomposes S1P. Mechanistically, S1P binds its receptor, a family of G protein-coupled receptors, and activates PI3K-Akt-eNOS signaling. Endothelial lipase appears to augment the S1P effect on angiogenesis (refer to the detailed review on S1P and vascular function previously published), but more studies are needed to determine how endothelial lipase enhances S1P function.
In addition to HDL, low-density lipoprotein (LDL) has also been reported to govern angiogenesis. Microsomal triglyceride transfer protein (MTP) mutation that results in low LDL-cholesterol (LDL-C) is found to increase zebrafish angiogenesis. MTP is a lipid transfer protein that assembles apoB-containing very LDL (VLDL) in the liver or chylomicrons in the intestine. The dysregulated angiogenesis phenotype in Mtp mutant animals is due to downregulation of VEGFR1, the decoy receptor for VEGFA, resulting in greater VEGFA availability. The mechanism of how LDL contributes to VEGFR1 upregulation is not clear yet. The pro-angiogenesis effect of Mtp deficiency, however, is not observed in MO-mediated MTP knockdown zebrafish. Although MTP knockdown reduces LDL-C levels, the residual enzyme in the morphants may compensate to an extent that confers insufficient penetration of angiogenesis defects.
Loss of the VLDL receptor in retinas causes excessive angiogenesis in the subretinal space and penetration of blood vessels in the photoreceptor layers., However, usually, VLDL will be catabolized rapidly in the peripheral circulation and cannot enter the brain, thus other apoE-containing lipoproteins that are synthesized de novo in the brain may be responsible for this effect.
Hypercholesterolemia increases EPC counts and promotes reendothelialization. The greater EPC numbers may be due to their differentiation from a higher frequency of HSPCs present in a hypercholesterolemic setting. In vitro cholesterol dose dependently augments EPC function including proliferation, migration, and adhesion and increases proangiogenic VEGFA expression but reduces anti-angiogenic Notch1 expression.
| Apoa-I-Binding Protein: A Novel Protein Connects Cholesterol Efflux With Angiogenesis|| |
AIBP, encoded by APOA1BP, is a secreted protein that physically associates with apoA-I and HDL. In addition, AIBP is also localized in the mitochondria and is identified as the epimerase that functions in damaged NAD (P) H repair, where AIBP catalyzes the conversion of R-NAD (P) H-hydrate (NAD [P] HX) to S-NAD (P) HX and an ATP-dependent dehydratase converts the latter to a functional NAD (P) H.,,,,, AIBP mutation precipitates neurometabolic disorder and lethality in infants, which is hypothesized to be caused by the formation of the presumptive toxic metabolite cyclic NADHX or mitochondrial dysfunction. Loss or mutation of AIBP orthologues in Escherichia More Details coli, Saccharomyces cerevisiae, and Arabidopsis thaliana confers no observable growth phenotype.,,,,,, This is unexpected given the importance and conservation of NAD (P) H metabolism and mitochondrial function. Since the in vivo cause-effect relationship of this enzymatic activity with human pathophysiology is unclear, we prefer to call it AIBP and focus on its cholesterol metabolism function in this review. A recent study suggests a possible moonlight function of an AIBP ortholog in E. coli B6 metabolism, which will need further detailed characterization. AIBP has a paralog, known as YJEFN3 or AIBP2. Aibp2 depletion in zebrafish increases cellular cholesterol content, and this observation is validated in a Genome RNAi screen database using human cells and Drosophila (http://www. genomernai. org/v17/genedetails/2/374887). We identified the role of AIBP in accelerating cholesterol efflux to HDL in ECs. AIBP, by increasing the overall HDL-binding capacity to ECs, but reducing the HDL-binding affinity, creates a situation favoring cholesterol efflux. The AIBP effect on cholesterol efflux to apoA-I is verified in macrophages and is shown to impede lipid raft-associated inflammatory signaling.,, The mechanism by which AIBP accelerates cholesterol efflux needs further investigation. Ongoing study in our laboratory suggests that AIBP binds ECs in a saturable fashion; thus, we postulate that AIBP binds EC through a yet-to-be identified receptor and mediates targeted cholesterol efflux, which reduces lipid raft/caveolae abundance, inhibits VEGFR2 activation, and limits angiogenesis [Figure 1].,
We have characterized the function of AIBP and its zebrafish paralog AIBP2 in blood vessel formation, which may be implicated in preeclampsia and other genetic disorders., Knockdown of AIBP2 in zebrafish increases vascular lipid raft content, bolsters VEGFR2 signaling, and augments angiogenesis in different vascular beds in zebrafish. The absence of cholesterol transporters – Abca1 and Abcg1 phenocopies increases angiogenesis in AIBP2-deficient animals. Conversely, forced AIBP2 expression restricts angiogenic sprouting in an ABCA1- and ABCG1-dependent manner. Raising HDL levels rescues higher membrane lipid order in zebrafish. In line with the zebrafish study, AIBP knockout increases murine retinal angiogenesis in postnatal development, an effect that can be reversed by apoA-I overexpression. Similarly, AIBP deficiency elevates pathological angiogenesis in an in vivo Matrigel angiogenesis model, increases capillary vessel formation, and enhances recovery of perfusion in the hindlimb ischemia model. Mechanistically, AIBP limits angiogenesis through restricting the proangiogenic VEGFR2 activation and enhancing the anti-angiogenic Notch signaling., In contrast to VEGFR2, lipid raft disruption enhances codistribution of the Notch receptor and its activator protease γ-secretase in nonrafts, which facilitates Notch cleavage and transcriptional activation. While our study in retinal ECs and other studies in neurons show that modest reduction of cholesterol levels increases the products of γ-secretase-mediated proteolytic cleavage, for example, Notch intracellular domain or β amyloid peptide, some studies suggest that lipid rafts augment γ-secretase activity in vitro. Disruption of lipid rafts using 19, 20-dihydroxydocosapentaenoic acid impedes Notch signaling. The extent of lipid raft disruption or optimal content of lipid rafts may account for the disparate observations of Notch activation.
| Effect of Statins on Angiogenesis|| |
Statins, HMG CoA reductase inhibitors, are a class of cholesterol-lowering drugs. They reduce plasma LDL-C levels by increasing liver LDL receptor expression. Interestingly, statins have been reported by multiple studies to regulate angiogenesis. One mechanism is that atorvastatin, when administered at a low concentration (0.01–0.1 μM), bolsters the PI3K-Akt signaling axis, which enhances the migration of EC, thereby increasing angiogenesis., However, high concentrations (>0.1 μM) trigger EC apoptosis, impede EC migration, and suppress angiogenesis. Another study suggests that statins increase HSPC numbers and thus the according differentiation of EPC, an effect that is dependent on greater Akt activation but not on RhoA or eNOS activity [Figure 3]. Atorvastatin treatment also reduces lipid rafts/caveolae content, which disrupts the inhibitory effect of Cav-1 on eNOS and bolsters eNOS activity and NO production. While these studies do not show a selectivity of statins on EC type, an interesting study in zebrafish reported that one HMGCR inhibitor, aplexone, selectively inhibits venous but not arterial angiogenesis. At the molecular level, this effect is dependent on geranylgeranylation of Rac and RhoA that preferentially occurs in venous but not arterial ECs. Since Bmp2 expression is the primary signal that controls venous angiogenic sprouting in zebrafish, it is tempting to speculate that a possible crosstalk exists between BMP signaling and cholesterol metabolism, which primes a dependence of protein prenylation for proper venous EC migration.
|Figure 3: Statins regulate angiogenesis through protein prenylation-regulated PI3K-Akt-eNOS signaling cascade or Cav-1-regulated eNOS activity. HMGCR: HMG CoA reductase. In addition, statins also reduce cell cholesterol levels, which may reduce lipid raft content and Cav-1-eNOS interaction, thereby alleviating the inhibition on eNOS and enhancing its activation|
Click here to view
| Liver X Receptor α/ β Transcriptionally or Noncanonically Regulates Angiogenesis|| |
As previously discussed, cholesterol transporters – ABCA1 and ABCG1 regulate angiogenesis, but it is not unexpected that their upstream regulator – LXRα/β also functions in neovascularization [Figure 4]. Indeed, treatment with LXR agonists inhibits EC migration and in vitro angiogenesis. Mechanistically, LXR-induced expression of ABCA1 and ABCG1 augments cholesterol efflux from EC, which disrupts lipid rafts-anchored VEGFR2 signaling. A similar mechanism for LXR-mediated ABCA1-dependent anti-inflammatory effect is proposed in macrophages. A recent study suggests another mechanism for LXR-regulated angiogenesis involving lipoprotein apoD, which is identified as a novel target of LXR. SR-BI is found to interact with apoD and mediate the effect of apoD on angiogenesis, and apoD gain-of-function interferes with Akt and mTOR activation [Figure 4]. In addition, LXRβ has also been reported to modulate angiogenesis independent of transcription activation. In this study, LXRβ interacts with the ERα ligand-binding domain. After PI3K/Akt-mediated phosphorylation at ERα S118, which in turn translocates to the cell surface caveolae, activates eNOS, promotes EC migration, and facilitates carotid artery revascularization in a perivascular injury model [Figure 4]. Since within the caveolae microdomains Cav-1 inhibits eNOS activity,,, it will be interesting to determine if the extranuclear LXRβ/ERα complex has any effect on Cav-1 and eNOS interaction. In addition, LXR activation increases VEGFA expression in macrophages and adipose tissue, which is independent of its putative transcription factor HIFa, but instead may be dependent on LXR/retinoid X receptor heterodimer transactivation of VEGFA. The in vivo significance of this pathway is unclear since inflammatory angiogenesis is not affected in mice with LXRs null macrophages.
|Figure 4: Liver X receptors control angiogenesis through transcription-dependent and transcription-independent effect on angiogenesis. Ligand-engaged liver X receptor α/β heterodimerize with retinoid X receptor and binds ABCG1 promoter and upregulates ABCG1 expression and accelerates cell surface cholesterol removal, thereby reducing plasma membrane lipid raft content and inhibits angiogenesis. Liver X receptor α/β activation also upregulates apoD, which inhibits Akt activation and limits angiogenesis. In addition, liver X receptor β has been shown to interact with ERα, which then activates Akt-eNOS signaling and augments endothelial cell migration and re-endothelialization. HC: Hydroxycholesterol|
Click here to view
| Cholesterol-Modified Sonic Hedgehog Regulates Angiogenesis in a Canonical and Noncanonical Fashion|| |
Shh is another cholesterol-regulated pathway for angiogenesis, in which the maturation of the Shh ligand requires cholesterol modification at its C-terminus. Canonical Shh signaling initiates with Shh binding its putative receptor Patched1, which then releases its inhibition of the co-receptor Smoothened and activates transcription factor Gli1-mediated transcriptional events. Shh augments angiogenesis in development and in hindlimb ischemia, which involves a relay of angiogenic cytokines that are released from interstitial mesenchymal cells, including VEGFA and angiopoietin1/2. Furthermore, Shh-VEGF-Notch is an essential signal axis that dictates arterial EC identity and orchestrates intersegmental angiogenesis. Studies using HUVEC or cardiac capillary EC documents a direct effect of Shh on angiogenic signaling, which activates noncanonical Shh signaling involving PI3K or RhoA activation., In skeletal ischemia or diabetic wound healing, activation of Shh-regulated angiogenesis program facilitates neovessel formation in the affected tissue., Cell therapy using CD34+ human HSPC overexpressing Shh demonstrates a salutatory effect on preserving cardiac function following acute myocardial infarction, which requires a paracrine effect of Shh-containing exosomes secreted from the transplanted CD34+ cells. Interestingly, the absence of Shh pathway activation also paradoxically increases capillary density in the regenerated skeletal muscles of a murine hindlimb ischemia model. Mechanistically, loss of Shh expression results in myocytes-induced macrophage infiltration, which secretes VEGFA to promote angiogenesis. The differential effect of Shh on angiogenesis in tissue ischemia could be another example of achieving optimal signaling within a defined range of ligand concentration and/or mouse strain as well as vascular bed differences. PDGF-BB appears to be the upstream signal that induces Shh expression in an in vitro and in vivo corneal angiogenesis model. In this model, ERK1/2 and Akt are the two effectors that transduce the Shh signal.
| Conclusion|| |
Cholesterol metabolism has been shown to regulate angiogenesis, and future application of the insight gained from cholesterol-regulated angiogenesis, either alone or in combination with existing treatment regimens, may improve outcomes of patients in targeting pathological angiogenesis. For example, since atorvastatin shows a biphasic effect on angiogenesis, would a period of a low dose treatment regimen benefit coronary artery disease patients to a greater extent? Would incorporating the information of S1P content on HDL contributes to a more effective treatment for cardiovascular disease? Targeting LXR is predicted to achieve dual salutary effects by impeding inflammation and restricting angiogenesis. AIBP is a particular protein of consideration for improving endothelial function because (1) it is an extracellular protein that is more amenable for targeting; (2) it effectively interferes with both angiogenesis and inflammation by enhancing HDL functionality; and (3) its depletion promotes functional angiogenesis that retains vascular integrity. Further investigation of the AIBP receptor and its role in AIBP-regulated angiogenesis will provide more therapeutic targets and guide development of new strategies for treatment of diseases associated with dysregulated angiogenesis.
This work is supported by grants (HL114734, HL132155, 16BGIA27790081, and 18TPA34250009) to L. F.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Chung AS, Ferrara N. Developmental and pathological angiogenesis. Annu Rev Cell Dev Biol 2011;27:563-84.
Hogan BM, Schulte-Merker S. How to plumb a pisces: Understanding vascular development and disease using zebrafish embryos. Dev Cell 2017;42:567-83.
Potente M, Carmeliet P. The link between angiogenesis and endothelial metabolism. Annu Rev Physiol 2017;79:43-66.
Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 2007;8:464-78.
Wacker A, Gerhardt H. Endothelial development taking shape. Curr Opin Cell Biol 2011;23:676-85.
Oram JF, Lawn RM, Garvin MR, Wade DP. ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. J Biol Chem 2000;275:34508-11.
Wang N, Silver DL, Costet P, Tall AR. Specific binding of apoA-I, enhanced cholesterol efflux, and altered plasma membrane morphology in cells expressing ABC1. J Biol Chem 2000;275:33053-8.
Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W, et al.
The gene encoding ATP-binding cassette transporter 1 is mutated in tangier disease. Nat Genet 1999;22:347-51.
Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, et al.
Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 1999;22:352-5.
Klucken J, Büchler C, Orsó E, Kaminski WE, Porsch-Ozcürümez M, Liebisch G, et al.
ABCG1 (ABC8), the human homolog of the Drosophila
white gene, is a regulator of macrophage cholesterol and phospholipid transport. Proc Natl Acad Sci U S A 2000;97:817-22.
Wang N, Lan D, Chen W, Matsuura F, Tall AR. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc Natl Acad Sci U S A 2004;101:9774-9.
Whetzel AM, Sturek JM, Nagelin MH, Bolick DT, Gebre AK, Parks JS, et al.
ABCG1 deficiency in mice promotes endothelial activation and monocyte-endothelial interactions. Arterioscler Thromb Vasc Biol 2010;30:809-17.
Yvan-Charvet L, Pagler T, Gautier EL, Avagyan S, Siry RL, Han S, et al.
ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 2010;328:1689-93.
Zhu X, Owen JS, Wilson MD, Li H, Griffiths GL, Thomas MJ, et al.
Macrophage ABCA1 reduces myD88-dependent toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol. J Lipid Res 2010;51:3196-206.
Murphy AJ, Bijl N, Yvan-Charvet L, Welch CB, Bhagwat N, Reheman A, et al.
Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis. Nat Med 2013;19:586-94.
Westerterp M, Tsuchiya K, Tattersall IW, Fotakis P, Bochem AE, Molusky MM, et al.
Deficiency of ATP-binding cassette transporters A1 and G1 in endothelial cells accelerates atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2016;36:1328-37.
O'Connell BJ, Denis M, Genest J. Cellular physiology of cholesterol efflux in vascular endothelial cells. Circulation 2004;110:2881-8.
Fang L, Choi SH, Baek JS, Liu C, Almazan F, Ulrich F, et al.
Control of angiogenesis by AIBP-mediated cholesterol efflux. Nature 2013;498:118-22.
Chung S, Sawyer JK, Gebre AK, Maeda N, Parks JS. Adipose tissue ATP binding cassette transporter A1 contributes to high-density lipoprotein biogenesis in vivo
. Circulation 2011;124:1663-72.
Timmins JM, Lee JY, Boudyguina E, Kluckman KD, Brunham LR, Mulya A, et al.
Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I. J Clin Invest 2005;115:1333-42.
Yvan-Charvet L, Ranalletta M, Wang N, Han S, Terasaka N, Li R, et al.
Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. J Clin Invest 2007;117:3900-8.
Wang X, Collins HL, Ranalletta M, Fuki IV, Billheimer JT, Rothblat GH, et al.
Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo
. J Clin Invest 2007;117:2216-24.
Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, et al.
Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 1999;22:336-45.
Noghero A, Perino A, Seano G, Saglio E, Lo Sasso G, Veglio F, et al.
Liver X receptor activation reduces angiogenesis by impairing lipid raft localization and signaling of vascular endothelial growth factor receptor-2. Arterioscler Thromb Vasc Biol 2012;32:2280-8.
Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 2016;17:611-25.
Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, et al.
Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 2010;465:483-6.
Eichmann A, Simons M. VEGF signaling inside vascular endothelial cells and beyond. Curr Opin Cell Biol 2012;24:188-93.
Pasula S, Cai X, Dong Y, Messa M, McManus J, Chang B, et al.
Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling. J Clin Invest 2012;122:4424-38.
Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, et al.
Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 2001;293:2449-52.
Razani B, Engelman JA, Wang XB, Schubert W, Zhang XL, Marks CB, et al.
Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J Biol Chem 2001;276:38121-38.
Feng L, Liao WX, Luo Q, Zhang HH, Wang W, Zheng J, et al.
Caveolin-1 orchestrates fibroblast growth factor 2 signaling control of angiogenesis in placental artery endothelial cell caveolae. J Cell Physiol 2012;227:2480-91.
Sonveaux P, Martinive P, DeWever J, Batova Z, Daneau G, Pelat M, et al.
Caveolin-1 expression is critical for vascular endothelial growth factor-induced ischemic hindlimb collateralization and nitric oxide-mediated angiogenesis. Circ Res 2004;95:154-61.
Wang Y, Roche O, Xu C, Moriyama EH, Heir P, Chung J, et al.
Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1. Proc Natl Acad Sci U S A 2012;109:4892-7.
Woodman SE, Ashton AW, Schubert W, Lee H, Williams TM, Medina FA, et al.
Caveolin-1 knockout mice show an impaired angiogenic response to exogenous stimuli. Am J Pathol 2003;162:2059-68.
Chang SH, Feng D, Nagy JA, Sciuto TE, Dvorak AM, Dvorak HF, et al.
Vascular permeability and pathological angiogenesis in caveolin-1-null mice. Am J Pathol 2009;175:1768-76.
Labrecque L, Royal I, Surprenant DS, Patterson C, Gingras D, Béliveau R, et al.
Regulation of vascular endothelial growth factor receptor-2 activity by caveolin-1 and plasma membrane cholesterol. Mol Biol Cell 2003;14:334-47.
Lin MI, Yu J, Murata T, Sessa WC. Caveolin-1-deficient mice have increased tumor microvascular permeability, angiogenesis, and growth. Cancer Res 2007;67:2849-56.
Feron O, Belhassen L, Kobzik L, Smith TW, Kelly RA, Michel T. Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J Biol Chem 1996;271:22810-4.
García-Cardeña G, Fan R, Stern DF, Liu J, Sessa WC. Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J Biol Chem 1996;271:27237-40.
Shaul PW, Smart EJ, Robinson LJ, German Z, Yuhanna IS, Ying Y, et al.
Acylation targets emdothelial nitric-oxide synthase to plasmalemmal caveolae. J Biol Chem 1996;271:6518-22.
Papapetropoulos A, García-Cardeña G, Madri JA, Sessa WC. Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest 1997;100:3131-9.
Jadeski LC, Lala PK. Nitric oxide synthase inhibition by N (G)-nitro-L-arginine methyl ester inhibits tumor-induced angiogenesis in mammary tumors. Am J Pathol 1999;155:1381-90.
Lee PC, Salyapongse AN, Bragdon GA, Shears LL 2nd
, Watkins SC, Edington HD, et al.
Impaired wound healing and angiogenesis in eNOS-deficient mice. Am J Physiol 1999;277:H1600-8.
Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C, et al.
Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest 1998;101:2567-78.
Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM, et al.
Activation of nitric oxide synthase in endothelial cells by akt-dependent phosphorylation. Nature 1999;399:601-5.
Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al.
Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999;399:597-601.
Jozkowicz A, Cooke JP, Guevara I, Huk I, Funovics P, Pachinger O, et al.
Genetic augmentation of nitric oxide synthase increases the vascular generation of VEGF. Cardiovasc Res 2001;51:773-83.
Terasaka N, Westerterp M, Koetsveld J, Fernández-Hernando C, Yvan-Charvet L, Wang N, et al.
ATP-binding cassette transporter G1 and high-density lipoprotein promote endothelial NO synthesis through a decrease in the interaction of caveolin-1 and endothelial NO synthase. Arterioscler Thromb Vasc Biol 2010;30:2219-25.
Mao R, Meng S, Gu Q, Araujo-Gutierrez R, Kumar S, Yan Q, et al.
AIBP limits angiogenesis through γ-secretase-mediated upregulation of notch signaling. Circ Res 2017;120:1727-39.
Yang ST, Kreutzberger AJ, Lee J, Kiessling V, Tamm LK. The role of cholesterol in membrane fusion. Chem Phys Lipids 2016;199:136-43.
Sorci-Thomas MG, Owen JS, Fulp B, Bhat S, Zhu X, Parks JS, et al.
Nascent high density lipoproteins formed by ABCA1 resemble lipid rafts and are structurally organized by three apoA-I monomers. J Lipid Res 2012;53:1890-909.
Gao F, Vasquez SX, Su F, Roberts S, Shah N, Grijalva V, et al.
L-5F, an apolipoprotein A-I mimetic, inhibits tumor angiogenesis by suppressing VEGF/basic FGF signaling pathways. Integr Biol (Camb) 2011;3:479-89.
Zamanian-Daryoush M, Lindner D, Tallant TC, Wang Z, Buffa J, Klipfell E, et al.
The cardioprotective protein apolipoprotein A1 promotes potent anti-tumorigenic effects. J Biol Chem 2013;288:21237-52.
Cannizzo CM, Adonopulos AA, Solly EL, Ridiandries A, Vanags LZ, Mulangala J, et al.
VEGFR2 is activated by high-density lipoproteins and plays a key role in the proangiogenic action of HDL in ischemia. FASEB J 2018;32:2911-22.
Prosser HC, Tan JT, Dunn LL, Patel S, Vanags LZ, Bao S, et al.
Multifunctional regulation of angiogenesis by high-density lipoproteins. Cardiovasc Res 2014;101:145-54.
Huang CY, Lin FY, Shih CM, Au HK, Chang YJ, Nakagami H, et al.
Moderate to high concentrations of high-density lipoprotein from healthy subjects paradoxically impair human endothelial progenitor cells and related angiogenesis by activating Rho-associated kinase pathways. Arterioscler Thromb Vasc Biol 2012;32:2405-17.
Saddar S, Carriere V, Lee WR, Tanigaki K, Yuhanna IS, Parathath S, et al.
Scavenger receptor class B type I is a plasma membrane cholesterol sensor. Circ Res 2013;112:140-51.
González-Pecchi V, Valdés S, Pons V, Honorato P, Martinez LO, Lamperti L, et al.
Apolipoprotein A-I enhances proliferation of human endothelial progenitor cells and promotes angiogenesis through the cell surface ATP synthase. Microvasc Res 2015;98:9-15.
Christoffersen C, Nielsen LB. Apolipoprotein M: Bridging HDL and endothelial function. Curr Opin Lipidol 2013;24:295-300.
Christoffersen C, Obinata H, Kumaraswamy SB, Galvani S, Ahnström J, Sevvana M, et al.
Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. Proc Natl Acad Sci U S A 2011;108:9613-8.
Liu M, Seo J, Allegood J, Bi X, Zhu X, Boudyguina E, et al.
Hepatic apolipoprotein M (apoM) overexpression stimulates formation of larger apoM/sphingosine 1-phosphate-enriched plasma high density lipoprotein. J Biol Chem 2014;289:2801-14.
Ruiz M, Frej C, Holmér A, Guo LJ, Tran S, Dahlbäck B, et al.
High-density lipoprotein-associated apolipoprotein M limits endothelial inflammation by delivering sphingosine-1-phosphate to the sphingosine-1-phosphate receptor 1. Arterioscler Thromb Vasc Biol 2017;37:118-29.
Swendeman SL, Xiong Y, Cantalupo A, Yuan H, Burg N, Hisano Y, et al.
An engineered S1P chaperone attenuates hypertension and ischemic injury. Sci Signal 2017;10. pii: eaal2722.
Yanagida K, Hla T. Vascular and immunobiology of the circulatory sphingosine 1-phosphate gradient. Annu Rev Physiol 2017;79:67-91.
Tatematsu S, Francis SA, Natarajan P, Rader DJ, Saghatelian A, Brown JD, et al.
Endothelial lipase is a critical determinant of high-density lipoprotein-stimulated sphingosine 1-phosphate-dependent signaling in vascular endothelium. Arterioscler Thromb Vasc Biol 2013;33:1788-94.
Jamil H, Dickson JK Jr., Chu CH, Lago MW, Rinehart JK, Biller SA, et al.
Microsomal triglyceride transfer protein. Specificity of lipid binding and transport. J Biol Chem 1995;270:6549-54.
Avraham-Davidi I, Ely Y, Pham VN, Castranova D, Grunspan M, Malkinson G, et al.
ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1. Nat Med 2012;18:967-73.
Schlegel A, Stainier DY. Microsomal triglyceride transfer protein is required for yolk lipid utilization and absorption of dietary lipids in zebrafish larvae. Biochemistry 2006;45:15179-87.
Jiang A, Hu W, Meng H, Gao H, Qiao X. Loss of VLDL receptor activates retinal vascular endothelial cells and promotes angiogenesis. Invest Ophthalmol Vis Sci 2009;50:844-50.
Xia CH, Lu E, Liu H, Du X, Beutler B, Gong X. The role of vldlr in intraretinal angiogenesis in mice. Invest Ophthalmol Vis Sci 2011;52:6572-9.
Ii M, Takeshita K, Ibusuki K, Luedemann C, Wecker A, Eaton E, et al.
Notch signaling regulates endothelial progenitor cell activity during recovery from arterial injury in hypercholesterolemic mice. Circulation 2010;121:1104-12.
Ritter M, Buechler C, Boettcher A, Barlage S, Schmitz-Madry A, Orsó E, et al.
Cloning and characterization of a novel apolipoprotein A-I binding protein, AI-BP, secreted by cells of the kidney proximal tubules in response to HDL or apoA-I. Genomics 2002;79:693-702.
Giaever G, Chu AM, Ni L, Connelly C, Riles L, Véronneau S, et al.
Functional profiling of the Saccharomyces cerevisiae
genome. Nature 2002;418:387-91.
Kremer LS, Danhauser K, Herebian D, Petkovic Ramadža D, Piekutowska-Abramczuk D, Seibt A, et al.
NAXE mutations disrupt the cellular NAD(P)HX repair system and cause a lethal neurometabolic disorder of early childhood. Am J Hum Genet 2016;99:894-902.
Marbaix AY, Noël G, Detroux AM, Vertommen D, Van Schaftingen E, Linster CL, et al.
Extremely conserved ATP- or ADP-dependent enzymatic system for nicotinamide nucleotide repair. J Biol Chem 2011;286:41246-52.
Nichols RJ, Sen S, Choo YJ, Beltrao P, Zietek M, Chaba R, et al.
Phenotypic landscape of a bacterial cell. Cell 2011;144:143-56.
Niehaus TD, Richardson LG, Gidda SK, ElBadawi-Sidhu M, Meissen JK, Mullen RT, et al.
Plants utilize a highly conserved system for repair of NADH and NADPH hydrates. Plant Physiol 2014;165:52-61.
Colinas M, Shaw HV, Loubéry S, Kaufmann M, Moulin M, Fitzpatrick TB, et al.
A pathway for repair of NAD (P) H in plants. J Biol Chem 2014;289:14692-706.
Breslow DK, Cameron DM, Collins SR, Schuldiner M, Stewart-Ornstein J, Newman HW, et al.
A comprehensive strategy enabling high-resolution functional analysis of the yeast genome. Nat Methods 2008;5:711-8.
Hillenmeyer ME, Fung E, Wildenhain J, Pierce SE, Hoon S, Lee W, et al.
The chemical genomic portrait of yeast: Uncovering a phenotype for all genes. Science 2008;320:362-5.
Niehaus TD, Elbadawi-Sidhu M, Huang L, Prunetti L, Gregory JF 3rd
, de Crécy-Lagard V, et al.
Evidence that the metabolite repair enzyme NAD (P) HX epimerase has a moonlighting function. Biosci Rep 2018;38. pii: BSR20180223.
Zhang M, Li L, Xie W, Wu JF, Yao F, Tan YL, et al.
Apolipoprotein A-1 binding protein promotes macrophage cholesterol efflux by facilitating apolipoprotein A-1 binding to ABCA1 and preventing ABCA1 degradation. Atherosclerosis 2016;248:149-59.
Zhang M, Zhao GJ, Yao F, Xia XD, Gong D, Zhao ZW, et al.
AIBP reduces atherosclerosis by promoting reverse cholesterol transport and ameliorating inflammation in apoE-/- mice. Atherosclerosis 2018;273:122-30.
Zhang M, Zhao GJ, Yin K, Xia XD, Gong D, Zhao ZW, et al.
Apolipoprotein A-1 binding protein inhibits inflammatory signaling pathways by binding to apolipoprotein A-1 in THP-1 macrophages. Circ J 2018;82:1396-404.
Fang L, Miller YI. Targeted cholesterol efflux. Cell Cycle 2013;12:3345-6.
Aleksiūnienė B, Preiksaitiene E, Morkūnienė A, Ambrozaitytė L, Utkus A. A de novo
1q22q23.1 interstitial microdeletion in a girl with intellectual disability and multiple congenital anomalies including congenital heart defect. Cytogenet Genome Res 2018;154:6-11.
Mistry HD, Kurlak LO, Mansour YT, Zurkinden L, Mohaupt MG, Escher G, et al.
Increased maternal and fetal cholesterol efflux capacity and placental CYP27A1 expression in preeclampsia. J Lipid Res 2017;58:1186-95.
Abad-Rodriguez J, Ledesma MD, Craessaerts K, Perga S, Medina M, Delacourte A, et al.
Neuronal membrane cholesterol loss enhances amyloid peptide generation. J Cell Biol 2004;167:953-60.
Urano Y, Hayashi I, Isoo N, Reid PC, Shibasaki Y, Noguchi N, et al.
Association of active gamma-secretase complex with lipid rafts. J Lipid Res 2005;46:904-12.
Hu J, Popp R, Frömel T, Ehling M, Awwad K, Adams RH, et al.
Müller glia cells regulate notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid. J Exp Med 2014;211:281-95.
Goldstein JL, Brown MS. A century of cholesterol and coronaries: From plaques to genes to statins. Cell 2015;161:161-72.
Urbich C, Dernbach E, Zeiher AM, Dimmeler S. Double-edged role of statins in angiogenesis signaling. Circ Res 2002;90:737-44.
Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, et al.
The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000;6:1004-10.
Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, et al.
HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001;108:391-7.
Feron O, Dessy C, Desager JP, Balligand JL. Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation 2001;103:113-8.
Choi J, Mouillesseaux K, Wang Z, Fiji HD, Kinderman SS, Otto GW, et al.
Aplexone targets the HMG-CoA reductase pathway and differentially regulates arteriovenous angiogenesis. Development 2011;138:1173-81.
Wiley DM, Kim JD, Hao J, Hong CC, Bautch VL, Jin SW, et al.
Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein. Nat Cell Biol 2011;13:686-92.
Ito A, Hong C, Rong X, Zhu X, Tarling EJ, Hedde PN, et al.
LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling. Elife 2015;4:e08009.
Lai CJ, Cheng HC, Lin CY, Huang SH, Chen TH, Chung CJ, et al.
Activation of liver X receptor suppresses angiogenesis via induction of ApoD. FASEB J 2017;31:5568-76.
Ishikawa T, Yuhanna IS, Umetani J, Lee WR, Korach KS, Shaul PW, et al.
LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity. J Clin Invest 2013;123:3488-97.
Ju H, Zou R, Venema VJ, Venema RC. Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J Biol Chem 1997;272:18522-5.
Michel JB, Feron O, Sacks D, Michel T. Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. J Biol Chem 1997;272:15583-6.
Walczak R, Joseph SB, Laffitte BA, Castrillo A, Pei L, Tontonoz P. Transcription of the vascular endothelial growth factor gene in macrophages is regulated by liver X receptors. J Biol Chem 2004;279:9905-11.
Nusse R. Wnts and hedgehogs: Lipid-modified proteins and similarities in signaling mechanisms at the cell surface. Development 2003;130:5297-305.
Briscoe J, Thérond PP. The mechanisms of hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 2013;14:416-29.
Pola R, Ling LE, Silver M, Corbley MJ, Kearney M, Blake Pepinsky R, et al.
The morphogen sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med 2001;7:706-11.
Lawson ND, Vogel AM, Weinstein BM. Sonic hedgehog and vascular endothelial growth factor act upstream of the notch pathway during arterial endothelial differentiation. Dev Cell 2002;3:127-36.
Chinchilla P, Xiao L, Kazanietz MG, Riobo NA. Hedgehog proteins activate pro-angiogenic responses in endothelial cells through non-canonical signaling pathways. Cell Cycle 2010;9:570-79.
Renault MA, Roncalli J, Tongers J, Thorne T, Klyachko E, Misener S, et al.
Sonic hedgehog induces angiogenesis via Rho kinase-dependent signaling in endothelial cells. J Mol Cell Cardiol 2010;49:490-8.
Asai J, Takenaka H, Kusano KF, Ii M, Luedemann C, Curry C, et al.
Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling. Circulation 2006;113:2413-24.
Pola R, Ling LE, Aprahamian TR, Barban E, Bosch-Marce M, Curry C, et al.
Postnatal recapitulation of embryonic hedgehog pathway in response to skeletal muscle ischemia. Circulation 2003;108:479-85.
Mackie AR, Klyachko E, Thorne T, Schultz KM, Millay M, Ito A, et al.
Sonic hedgehog-modified human CD34+cells preserve cardiac function after acute myocardial infarction. Circ Res 2012;111:312-21.
Caradu C, Guy A, James C, Reynaud A, Gadeau AP, Renault MA, et al.
Endogenous sonic hedgehog limits inflammation and angiogenesis in the ischaemic skeletal muscle of mice. Cardiovasc Res 2018;114:759-70.
Yao Q, Renault MA, Chapouly C, Vandierdonck S, Belloc I, Jaspard-Vinassa B, et al.
Sonic hedgehog mediates a novel pathway of PDGF-BB-dependent vessel maturation. Blood 2014;123:2429-37.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]