Received for publication June 8, 2006.
Revised July 21, 2006.
Accepted for publication July 21, 2006.

Fibroblast growth factor-2 mediates ACE inhibitor-induced angiogenesis in coronary endothelium

Abstract

The beneficial effect exerted by angiotensin converting enzyme inhibitors (ACEI) on vascular endothelium has been attributed to restoration of endothelial cell survival properties, and improvement of angiogenesis. Fibroblast growth factor-2 (FGF-2) is an angiogenic factor for the microvascular endothelium, which tonically promotes endothelial cell growth and survival through an autocrine/paracrine mechanism. Here we formulate the hypothesis that FGF-2 might contribute to the prosurvival/proangiogenic effect of ACEI. We investigated zofenoprilat and in selected experiments lisinopril, as representatives of ACEI. These compounds induced formation of pseudocapillaries in vessel fragments isolated from porcine coronary and human umbilical arteries, by increasing endothelial cell growth up to 5 fold. Angiogenesis was abolished by inhibitors of nitric oxide synthase (NOS) pathway and by anti-FGF-2 antibodies. Consistently, in cultured coronary endothelial cells (CVEC) ACEI up-regulated eNOS and FGF-2, and induced MAPK ERK1/2 activation. The overexpression of eNOS/FGF-2 produced, at the functional level, enhanced cell proliferation and migration, the latter effect being dose-dependent and maximal at 0,1 µM zofenoprilat. The importance of FGF-2 for the acquisition of the angiogenic phenotype elicited by ACEI was clearly demonstrated by the impairment of endothelial functions following transfection of CVEC with siRNA for FGF-2. Moreover, FGF-2 silencing greatly affected the nuclear translocation of the FGFR-1, highlighting the autocrine mode of action of FGF-2. At the endothelial membrane level, zofenoprilat appeared to activate the bradykinin B1 receptor, a known stimulant of FGF-2 expression. In conclusion we show that ACEI exert protective/proangiogenic effects in microvascular coronary endothelial cells by activating the endogenous FGF-2/FGFR-1 system.

Key words: ACE inhibitor, angiogenesis, autocrine control, endothelial cell, endothelial nitric oxide synthase, fibroblast growth factor-2

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