Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase.

Abstract

Nitric oxide (NO), constitutively produced by endothelial nitric oxide synthase (eNOS), plays a major role in the regulation of blood pressure and vascular tone. We generated transgenic mice overexpressing bovine eNOS in the vascular wall using murine preproendothelin-1 promoter. In transgenic lineages with three to eight transgene copies, bovine eNOS-specific mRNA, protein expression in the particulate fractions, and calcium-dependent NOS activity were confirmed by RNase protection assay, immunoblotting, and L -arginine/citrulline conversion. Immunohistochemical studies revealed that eNOS protein was predominantly localized in the endothelial cells of aorta, heart, and lung. Blood pressure was significantly lower in eNOS-overexpressing mice than in control littermates. In the transgenic aorta, basal NO release (estimated by N -nitro-L -arginine-induced facilitation of the contraction by prostaglandin F 2 ␣ ) and basal cGMP levels (measured by enzyme immunoassay) were significantly increased. In contrast, relaxations of transgenic aorta in response to acetylcholine and sodium nitroprusside were significantly attenuated, and the reduced vascular reactivity was associated with reduced response of cGMP elevation to these agents as compared with control aortas.

Endothelial nitric oxide synthase genetic variation and essential hypertension risk in Han Chinese: the Fangshan study

“…2 In contrast, induction of eNOS cDNA in mice reduced BP. 3 As the genomic sequence of eNOS is highly polymorphic, it is of added interest to these findings to confirm which variant(s) at eNOS might have a functional potential to affect the final bioavailability of eNOS, and thus the development of hypertension. Genetic association studies regarding the relationship between eNOS variants and hypertension, however, have yielded inconsistent results.…”

Reduction of Blood Pressure, Plasma Cholesterol, and Atherosclerosis by Elevated Endothelial Nitric Oxide

“…For example, NO produced by eNOS causes vasodilation. Thus, eNOS knockout mice are hypertensive (1), whereas eNOS transgenic mice have hypotension (2). In addition, NO reduces the activation and aggregation of platelets (3,4), attenuates adhesion of leukocytes to the endothelium (5-7), reduces the permeability of the endothelium, and inhibits proliferation and migration of vascular smooth muscle cells (8).…”

Endothelial nitric oxide synthase and nitric oxide regulate endothelial tissue factor expression in vivo in the sickle transgenic mouse

“…However, this requires some comment. The original [11] and later [12] testing of this transgenic mouse demonstrated enhanced eNOS expression mostly in endothelial cells of the aorta, heart, and lung. However, our results using BMT manipulation showed that there was a significant degree of eNOS activity in peripheral blood cells of the eNOS-Tg NY1DD whole animal.…”

“…When they were first established, these mice were described as the ''eNOS Tg-Kobe'' mouse [11] and were provided to us by Dr. David J. Leffer, Emory University [12]. In addition, eNOS 2/2 mice were obtained from Jackson Laboratories [35].…”