Abstract
Sexual dimorphisms are recognized in cardiovascular conditions such as hypertension, stroke, thrombosis and vasculitis. B-type natriuretic peptide (BNP) is a guanylyl cyclase A (GC-A) agonist. The anti-hypertensive, vasodilatory, anti-fibrotic, and anti-hypertrophic properties of BNP are well established in male animal models. Although circulating BNP levels are higher in women, when compared to age-matched men, the cardiovascular protective propensity of BNP in females is poorly understood. We assessed the cardiovascular consequences of BNP deletion in genetically null (Nppb−/−) female rat lines. Throughout the study, blood pressure (BP) remained uninfluenced by genotype, and cardiorenal consequences of BNP knock out remained minor. Unexpectedly, approximately 60% of Nppb−/− females developed mesenteric polyarteritis-nodosa (PAN)-like vasculitis in their life span, some as early as 4 months of age. Mesenteric lesions involved intense arterial remodeling, progressive inflammation, occluded lumens, and less frequently intestinal necrosis and multiple visceral arterial aneurysms. Cumulative pathologies resulted in a significant decline in survival of the Nppb−/− female. This study highlights BNP’s vasoprotective propensity, bringing to light a possible sex specific difference in the cardiovascular protection provided by BNP. Defects in the BNP/GC-A/cGMP pathway may play a role in arteriopathies in women, while GC-A agonists may provide effective therapy for arteritis.
Highlights
Gender differences, and sex hormones, are recognized factors involved in the frequency, clinical manifestation, and mortality of cardiovascular disease[1]
Increased cardiac fibrosis has been observed in both male B-type natriuretic peptide (BNP) knockout mice and rats[15,19], Trichrome staining of the female knock out cardiac tissues at 9 months identified no significant increase in cardiac fibrosis (Fig. 1D)
Androcentric reports of mouse models show that BNP knockout results in cardiac fibrosis[15]
Summary
Sex hormones, are recognized factors involved in the frequency, clinical manifestation, and mortality of cardiovascular disease[1]. B-type natriuretic peptide (BNP) is a cardiac hormone in the natriuretic peptide family, integral in protecting endothelial function[6] and maintaining pressure and volume of the cardiovascular system[7]. BNP can bind natriuretic peptide receptor C (Npr-C), nicknamed the clearance receptor, which does not lead to an increase in cGMP10. Others have shown male mice genetically null for BNP develop multi-focal cardiac fibrosis[15]. BNP deletion in male rats leads to adult-onset hypertension with myocardial hypertrophy, cardiac fibrosis and progressive hypertensive nephropathy[19]. Sustained BNP over-expression by cardiotropic adeno-associated vectors prolongs survival of male spontaneously hypertensive rats, and prevents the development of hypertensive heart disease[20,21]. There is a lack of studies addressing this gender difference, or the protective role of BNP specific to women. Our study highlights a novel and previously unrealized role for BNP in the etiology of, and possibly the sexual dimorphic nature of vascular diseases
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