Ovarian Hormones Moderate Systolic Hypertension in Female Eln 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 (ELN). Heterozygous deletion of Eln (Eln ^+/-) 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 Eln ^+/- mice. Here, we determined whether ovarian hormones play a role in sex-related difference in blood pressure elevation resulting from Eln haploinsufficiency. Female Eln ^+/+ and Eln ^+/- 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 Eln ^+/- mice, resulting in increased pulse pressure. In Eln ^+/- 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 Eln ^+/--induced hypertension may be Na⁺-dependent. We conclude that increased Na⁺ and water retention by the kidney contribute to hypertension resulting from Eln 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.