Statins and angiogenesis: is it about connections?
Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, have been shown to induce both angiogenic and angiostatic responses. We attempted to resolve this controversy by studying the effects of two different statins, rosuvastatin and simvastatin, in two different assay systems. In the matrigel angiogenesis assay, both statins enhanced tube formation by human umbilical vein endothelial cells (HUVECs, p<0.01 vs. control). In the ex vivo mouse aortic ring sprouting assay, both statins virtually abolished new vessel formation (p<0.01). As a basic difference between the two models of angiogenesis is dispersed state of endothelial cells vs. compact monolayer, we analyzed influence of statins on endothelial junction proteins. RT-PCR analysis and cytoimmunostaining of HUVECs treated with simvastatin revealed increased expression of VE-cadherin (p<0.05). The blockade of VE-cadherin with a specific antibody reversed simvastatin-induced tube formation (p<0.002). These data suggest that statins through VE-cadherin stimulation modulate cell-cell adhesion and diminish the ability of cells to proliferate and migrate. The observations of reduced angiogenesis in the intact vessel may relate to anti-atherosclerotic and anti-cancer effects of statins, and provide a feasible explanation for conflicting data under different experimental conditions.
Khaidakov
Magomed
M
Division of Cardiology, University of Arkansas for Medical Sciences and VA Medical Center, Little Rock, AR 72205, USA. mkhaidakov@uams.edu
Wang
Wenze
W
Khan
Junaid A
JA
Kang
Bum-Yong
BY
Hermonat
Paul L
PL
Mehta
Jawahar L
JL
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects*; D005464:Fluorobenzenes / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects; D000099152:Cadherin 5
D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D015820:Cadherins; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium; D019821:Simvastatin; D013449:Sulfonamides; D000099152:Cadherin 5