Neuronal and endothelial nitric oxide synthase gene knockout mice

Abstract

Targeted disruption of the neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) genes has led to knockout mice that lack these isoforms. These animal models have been useful to study the roles of nitric oxide (NO) in physiologic processes. nNOS knockout mice have enlarged stomachs and defects in the inhibitory junction potential involved in gastrointestinal motility. eNOS knockout mice are hypertensive and lack endothelium-derived relaxing factor activity. When these animals are subjected to models of focal ischemia, the nNOS mutant mice develop smaller infarcts, consistent with a role for nNOS in neurotoxicity following cerebral ischemia. In contrast, eNOS mutant mice develop larger infarcts, and show a more pronounced hemodynamic effect of vascular occlusion. The knockout mice also show that nNOS and eNOS isoforms differentially modulate the release of neurotransmitters in various regions of the brain. eNOS knockout mice respond to vessel injury with greater neointimal proliferation, confirming that reduced NO levels seen in endothelial dysfunction change the vessel response to injury. Furthermore, eNOS mutant mice still show a protective effect of female gender, indicating that the mechanism of this protection cannot be limited to upregulation of eNOS expression. The eNOS mutant mice also prove that eNOS modulates the cardiac contractile response to ß-adrenergic agonists and baseline diastolic relaxation. Atrial natriuretic peptide, upregulated in the hearts of eNOS mutant mice, normalizes cGMP levels and restores normal diastolic relaxation.

Endothelium-Independent Flow-Induced Dilation in the Mouse Carotid Artery

“…Our findings add to accumulating evidence that the response of arteries to shear is species and vessel dependent [5, 7, 8, 45, 61, 62] and can be either endothelium-dependent [5] or endothelium-independent [7, 8]. Even within a specific strain such as eNOS –/– mice, the specific mediator of flow-induced response varies according to the vessel studied [5, 6, 17].…”

“…Therefore, our present data suggest that flow regulation of vascular tone is enhanced in carotid arteries from the eNOS –/– mice. While flow-mediated dilation in other arteries of this knockout strain is mediated by nNOS [61], EDHF [5] or prostaglan dins [17], flow-induced relaxation in carotid arteries is not. Accordingly, the enhancement of flow dilation in eNOS –/– mice may be due to compensatory upregulation of the endothelium-independent component of flow response as an adaptation to low bioavailability of NO.…”

Role of Neuronal Nitric-Oxide Synthase in Estrogen-Induced Relaxation in Rat Resistance Arteries

“…Although the functional significance of nNOS in vascular cells is poorly understood, a few studies suggested its role in mediating vascular relaxation in isolated arteries (Capettini et al, 2008;Han et al, 2009). Whereas nNOS and eNOS share some common characteristics (e.g., constitutive expression, calcium-dependent activation, and NO generation), they also possess unique properties and may have distinct roles in vascular function (Huang, 1999;Melikian et al, 2009;Seddon et al, 2009). Similar to eNOS, a change in phosphorylation status determines nNOS enzymatic activity (Zhou and Zhu, 2009); however, little is known about activating (at Ser1417) versus inactivating (at Ser847) regulatory phospho-sites in endothelial nNOS.…”

“…As a vital neurotransmitter system in brain development, defective NO/nNOS function has been implicated in devastating neurodegenerative processes such as dementia (Zhou and Zhu, 2009). Other studies have linked nNOS hyperactivation to neuronal damage after cerebrovascular accident, i.e., stroke (Eliasson et al, 1999;Huang, 1999), suggesting a potential for nNOS inhibitors to ameliorate ischemic brain injury (Nanri et al, 1998). It is likely that understanding the role of vascular nNOS may as well uncover a far-reaching significance in health and/or disease.…”

O Óxido Nítrico (No) No Controle Neural Da Pressão Arterial: Modulação Da Transmissão Glutamatérgica No NTS

“…A nNOS está presente em nervos perivasculares (nervos nitrérgicos) de diversos vasos sanguíneos e constitui um mecanismo alternativo de produção de NO para controle do fluxo sanguíneo e resistência vascular independente da eNOS 30,31 . No SNC, o NO derivado desta nNOS estaria associado à regulação do fluxo sanguíneo cerebral, e as maiores densidades de nNOS estão geralmente co-localizadas a neurotransmissores vasoativos 30,32 .…”