Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS

Abstract

The rupture of cerebral aneurysm (CA) and subsequent subarachnoid hemorrhage can cause fatal results. Recent experimental findings have suggested that the mechanism of CA formation is based on chronic inflammation in arterial walls by hemodynamic force. Endothelial nitric oxide synthase (eNOS) protects arterial walls from vascular inflammation by relieving hemodynamic force through nitric oxide (NO) production. Thus, the expression and protective role of eNOS in CA formation have been investigated in this study. In this study, experimental induced rodent CA models by carotid ligation and systemic hypertension were used. The expression of eNOS was examined in rat CA models and revealed that it was decreased at the site of CA formation. Next, CA was induced in eNOS À/À mice to clarify the role of eNOS in CA formation. In eNOS À/À mice, the incidence of CA formation was similar to that found in wild-type mice. In CA walls of eNOS À/À mice, the expression of neuronal nitric oxide synthase (nNOS) was upregulated compared with that in wild-type mice, suggesting the compensatory effect of nNOS. Hence, eNOS À/À nNOS À/À mice were generated, underwent CA induction and confirmed that eNOS À/À nNOS À/À mice exhibited an increased incidence of CA formation accompanied by accelerated macrophage infiltration. These results suggested that the deficiency of eNOS could be compensated by nNOS upregulation in cerebral arteries and that the eNOS and nNOS complementarily had the protective role in CA formation. The results of this study will provide us with new insight about the mechanisms of CA formation and the functional redundancy between eNOS and nNOS in cerebral arteries.

Endothelial Nitric Oxide Synthase and Superoxide Mediate Hemodynamic Initiation of Intracranial Aneurysms

“…Specifically, mice with double knockout of eNOS and nNOS [13] have increased IA formation compared to wild type animals. However, rodents were primed with additional risk factors, including high salt diet and renal artery ligation to induce hypertension, which can upregulate inflammatory cytokines and promote inflammatory cell infiltration [40].…”

“…Previous studies have highlighted critical, yet contradictory roles for nitric oxide (NO) in regulating MMP induction in flow-dependent remodeling [13], [14]. Inhibiting NO synthesis decreased MMPs and reduced adaptive outward expansion in chronic flow-loaded arteries [14].…”

“…Inhibiting NO synthesis decreased MMPs and reduced adaptive outward expansion in chronic flow-loaded arteries [14]. However, knockout of eNOS in hypertensive rodents resulted in increased MMPs and IA formation [13]. On the other hand, superoxide and other reactive oxygen species (ROS) (e.g., peroxynitrite, a reaction product of NO and superoxide) induce MMP production [15] and activation [16] and also trigger SMC phenotype changes [17], [18].…”

Role of Fluid Dynamics and Inflammation in Intracranial Aneurysm Formation

“…Flow is a central process in many of the components of aneurysm formation. Flow determines where inflammatory cells will adhere and how the endothelium and its endothelial cells will respond to local inflammation 7–9 . The endothelium is the primary interfacial surface with flowing blood and the endothelial cells are premier sensors of shear from above and strain from below 10 .…”

Overlapping Biological Mechanisms Underlying Sickle Cell Disease, Stress, and Depression

“…Interestingly, research suggests that when eNOS levels are low, a compensation mechanism operates to increase the levels of neuronal nitric oxide synthase, another type of enzyme that is responsible for NO production in the brain. 80 Higher levels of neuronal nitric oxide synthase, however, are associated with increased risk of stroke, neurodegenerative diseases (i.e., schizophrenia, Parkinson's disease, and Alzheimer's disease), and pain. 81 The increased pain experienced by individuals with SCD and depression could be even greater than for individuals with depression alone due to the decreased availability of eNOS in SCD, and the corresponding decreased bioavailability of the neurotransmitters serotonin and norepinephrine, which normally provide inhibition of ascending pain signals.…”