P190Deficiency of non-endothelial eNOS causes hypertension in mice

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Abstract

Purpose: Despite irrefutable role of endothelial nitric oxide synthase (eNOS) in vascular smooth muscle tone, its contribution to the regulation of blood pressure has been proven mainly either by the global eNOS-deficiency or by the use of unspecific NOS-inhibitors. To distinguish the relevance of endothelial and non-endothelial eNOS, we generated a novel double transgenic mouse model lacking eNOS in all organs except the vascular endothelium. The aim of the study was to evaluate the contribution of non-endothelial eNOS to the regulation of blood pressure (BP).

Methods: To accomplish this a double transgenic strain expressing eNOS exclusively in the vascular endothelium has been generated (eNOS-Tg/KO) by endothelial-specific Tie-2 driven targeting of bovine eNOS in eNOS-deficient mice (eNOS-KO).

Results: Expression of eNOS was evaluated in aorta, myocardium, kidney, brain stem and skeletal muscle of eNOS-Tg/KO by western blot and real-time PCR. Organ bath studies revealed a complete normalization of aortic reactivity to acetylcholine (ACh), phenylephrine and the NO-donors SNAP and DEA/NO in eNOS-Tg/KO. Function of eNOS in resistance arteries was demonstrated by acute i.v. infusion of ACh and the NOS-inhibitor L-NAME. ACh decreased mean arterial pressure (MAP) in all strains but eNOS-KO responded significantly less sensitive as compared eNOS-Tg/KO and C57BL/6. Likewise, acute i.v. L-NAME application elevated MAP in C57BL/6 and eNOS-Tg/KO, but not in eNOS-KO. In striking contrast to these findings, basal mean, systolic and diastolic BPs in eNOS-Tg/KO remained significantly elevated and were similar to values of eNOS-KO. Chronic oral treatment with L-NAME increased BP to the level of eNOS-KO only in C57BL/6, but had no effect on hypertension in eNOS-KO and eNOS-Tg/KO.

Since there is considerable evidence that NO in the central nervous system affects sympathetic nerve activity and modulates BP we next sought to evaluate whether hypertension in eNOS-Tg/KO can be rescued by targeted reexpression of eNOS in the brain stem. Effects of stereotaxic coordinated microinjections of lentiviral particles encoding eNOS into the nucleus of the solitary tract (NTS) of the brain stem on systolic BP of eNOS-Tg/KO, eNOS-KO and C57BL/6 are currently under investigation.

Conclusions: The blood pressure lowering eNOS-mediated local vasodilator activity in resistance vessels alone cannot compensate for the lack of the non-endothelial eNOS-dependent component in the regulation of BP. These data demonstrate a previousely unrecognized role of extra-endothelial eNOS in the physiologic BP regulation.

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