Ovarian Hormones Moderate Systolic Hypertension in Female <i>Eln</i> Haploinsufficient Mice

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 (<i>ELN</i>). Heterozygous deletion of <i>Eln</i> (<i>Eln</i>^+/-) 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 female <i>Eln</i>^+/- mice. Here, we determined whether ovarian hormones play a role in sex-related difference in blood pressure elevation resulting from <i>Eln</i> haploinsufficiency. Female <i>Eln</i>^+/+ and <i>Eln</i>^+/- mice instrumented with radiotelemetry devices were subjected to sham surgery or ovariectomy (OVX). We found that OVX lowered diastolic but not systolic blood pressure (SBP) in <i>Eln</i>^+/- mice, resulting in increased pulse pressure. In <i>Eln</i>^+/- mice, diuresis induced by acute volume expansion was blunted, while anti-natriuresis was exaggerated. Furthermore, amiloride lowered SBP and increased urinary Na⁺ excretion, suggesting that <i>Eln</i>^+/--induced hypertension may be Na⁺-dependent. We conclude that increased Na⁺ and water retention by the kidney contribute to hypertension resulting from <i>Eln</i> haploinsufficiency. The underlying mechanism involves the alteration of ovarian hormone effects in the kidney and sustained signaling downstream of the V₂ receptor, leading to increased ENaC activity and water reabsorption.