Ovarian hormones moderate systolic hypertension in femalehaploinsufficient mice.

Abstract

Hypertension is a hallmark of cardiovascular abnormalities associated with Williams syndrome (WS), a rare genetic disorder involving microdeletion of genes on human chromosome 7, including the elastin gene (). Heterozygous deletion of() in mice recapitulates hypertension and arteriopathy associated with WS. Previously, differences in blood pressure elevation and sensitivity to dietary sodium were found to be less profound in femalemice. Here, we determined whether ovarian hormones play a role in sex-related differences in blood pressure elevation resulting fromhaploinsufficiency. Femaleandmice instrumented with radiotelemetry devices were subjected to sham surgery or ovariectomy (OVX). We found that OVX lowered diastolic but not systolic blood pressure (SBP) inmice, resulting in increased pulse pressure. Inmice, diuresis induced by acute volume expansion was blunted, whereas antinatriuresis was exaggerated. Furthermore, amiloride lowered SBP and increased urinary Naexcretion, suggesting that-induced hypertension may be Na-dependent. We conclude that increased Naand water retention by the kidney contribute to hypertension resulting fromhaploinsufficiency. The underlying mechanism involves the alteration of ovarian hormone effects in the kidney and sustained signaling downstream of the Vreceptor, leading to increased epithelial sodium channel (ENaC) activity and water reabsorption.This study uncovers novel renal mechanisms by whichhaploinsufficiency leads to systolic hypertension and the role of ovarian hormones in moderating blood pressure elevation. In femalehaploinsufficient mice, ovarian hormone depletion elevates systolic blood pressure.haploinsufficiency augments sodium and water reabsorption that is, in part, mediated by sustained activity of the vasopressin Vreceptor and is associated with ENaC-dependent blood pressure elevation. These findings implicate abnormal sodium and water handling by the kidney as a contributing mechanism besides arteriopathy as the primary drivers of hypertension resulting fromhaploinsufficiency.