Vol. 296, Issue 2, 473-477, February 2001

Vascular Endothelial Growth Factor-Mediated Endothelium-Dependent Relaxation Is Blunted in Spontaneously Hypertensive Rats

Ming-Hui Liu, Hong-Kui Jin, H. Storm Floten, Qin Yang, Anthony P. C. Yim, Anthony Furnary, Thomas F. Zioncheck, Stuart Bunting and Guo-Wei He

Cardiovascular Research, Starr Academic Center for Cardiac Surgery, Providence Heart Institute, St. Vincent Hospital, Portland, Oregon (M.-H.L., S.F., A.F., G.-W.H); Cardiovascular Research, Genentech, Inc. San Francisco, California (H.-K.J, T.F.Z, S.B.); and Cardiovascular Surgical Research Laboratory, Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China (Q.Y., A.P.C.Y., G.-W.H.)

The vasodilatory effect of VEGF has not been characterized in the setting of hypertension. This study investigated the in vitro vasorelaxant effects of VEGF in organ chambers in the aorta of the adult (12-week-old) spontaneously hypertensive rats (SHR), young (4-week-old) SHR without hypertension, and age-matched Wistar-Kyoto (WKY) rats compared with acetylcholine (ACh). Cumulative concentration-relaxation curves were established for VEGF (~10¹²-10^8.5 M) and ACh (~10¹⁰-10⁵ M) in U46619 (10⁸ M)-induced contraction. VEGF induced endothelium-dependent relaxation that was significantly reduced in the adult SHR compared with the age-matched WKY control (87.8 ± 2.8 versus 61.4 ± 8.6%, P = 0.01). These responses were significantly attenuated by pretreatment with N-nitro-L-arginine (L-NNA, 300 µM) alone (SHR: 25.1 ± 1.9%; WKY: 21.0 ± 2.6%; P = 0.01) or indomethacin (7 µM) + L-NNA (SHR: 30.2 ± 2.1%; WKY: 35.0 ± 2.9%; P = 0.01). Further addition of oxyhemoglobin (20 µM) abolished the residual relaxation and reduced the relaxation induced by nitroglycerin. ACh induced similar responses to VEGF. In contrast, pretreatment with indomethacin alone enhanced VEGF- or ACh-induced relaxations and the effect was greater in the adult SHR than in WKY rats. In contrast to the adult SHR versus WKY rats, there were no significant differences of VEGF- or ACh-induced relaxations between young SHR and WKY rats. The results demonstrate that VEGF induces endothelium- or nitric oxide-dependent relaxation, which is blunted in the adult SHR. The mechanism of this impairment may be related to decreased release of NO although increased release of contracting factors from the dysfunctional endothelium may also be involved.