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 (approximately 10(-12)-10(-8.5) M) and ACh (approximately 10(-10)-10(-5) M) in
U46619 (10(-8) 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(omega)-nitro-L-arginine (L-NNA, 300 microM) alone (SHR: 25.1 +/- 1.9%; WKY: 21.0 +/- 2.6%; P = 0.01) or
indomethacin (7 microM) + L-NNA (SHR: 30.2 +/- 2.1%; WKY: 35.0 +/- 2.9%; P = 0.01). Further addition of
oxyhemoglobin (20 microM) 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.