Aldosterone inhibits endothelial morphogenesis and angiogenesis through the downregulation of vascular endothelial growth factor receptor-2 expression subsequent to peroxisome proliferator-activated receptor gamma.
Angiogenesis plays a pivotal role in cardiovascular diseases such as ischemic heart disease, limb ischemia and heart failure, and has recently been shown to mediate various biological activities related to the pathogenesis of these diseases. In the present study, we evaluated the role of aldosterone in angiogenesis. Tube formation assay on Matrigel using human umbilical vein endothelial cells (HUVEC) revealed that aldosterone inhibited endothelial morphogenesis in a manner sensitive to eplerenone, a selective mineralocorticoid receptor antagonist. The anti-angiogenic effect of aldosterone was further confirmed by an in vivo angiogenesis assay using a Matrigel plug model in mice. Reverse transcription-mediated polymerase chain reaction and immunoblotting demonstrated that aldosterone downregulated the expression levels of vascular endothelial growth factor receptor-2 (VEGFR-2) and peroxisome proliferators-activated receptor gamma (PPAR gamma). VEGFR-2 expression was found to be enhanced in response to PPAR gamma activation by troglitazone, and attenuated by GW9662, a specific antagonist of PPAR gamma. In the tube formation assay, endothelial morphogenesis was stimulated by troglitazone, and inhibited by GW9662, indicating that PPAR gamma activation mediates positive regulation of angiogenesis through enhancement of VEGFR-2 expression. These data suggest that aldosterone inhibits angiogenesis through VEGFR-2 downregulation, subsequent to, at least in part, attenuation of PPAR gamma expression. The present findings provide a new insight into the possible therapeutic application of mineralocorticoid receptor blockade to various cardiovascular diseases.
Third Department of Internal Medicine, Faculty of Medical Sciences, Fukui University, 23-3 Matsuokashimoaizuki, Yoshida-gun, Fukui 910-1193, Japan.
Miki
M
Fujii
Isao
I
Inoki
Makoto
M
Saga
Norihiro
N
Morikawa
Ken-ichiro
K
Arakawa
Satoru
S
Inaba
Kazuaki
K
Yoshioka
Tadashi
T
Konoshita
Isamu
I
Miyamori
D000450:Aldosterone / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D003094:Collagen / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004338:Drug Combinations; D004727:Endothelium / Q000254:growth & development; D000077545:Eplerenone; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009024:Morphogenesis / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D011509:Proteoglycans / Q000494:pharmacology; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D007797:Laminin; D000451:Mineralocorticoid Receptor Antagonists; D047495:PPAR gamma; D011509:Proteoglycans; C059485:matrigel; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D003094:Collagen; D040301:Vascular Endothelial Growth Factor Receptor-2