LAUSR

William syndrome, an autosomal-dominant disease, is caused partly by loss-of-function mutations or gene macro-deletions resulting in elastin ( Eln ) haploinsufficiency. A major hallmark of Eln haploinsufficiency is hypertension, accompanied by arteriopathy and tortuous and elongated vessels. Previously, we showed that hypertension due to Eln haploinsufficiency in mice is due at least partly to abnormal remodeling of renal vascular signaling and increased blood pressure sensitivity to dietary salt observed only in male Eln +/- mice. In this study, we tested the hypothesis that ovarian hormones protect against excessive blood pressure increase resulting from Eln haploinsufficiency and blood pressure sensitivity to dietary salt in female mice. We used radiotelemetry to acquire diurnal blood pressure (BP) and heart rate (HR) before and after oophorectomy (OVX) in female wild type and Eln +/- mice. Four weeks after OVX, mice were placed on normal or high salt diet for 10 days, with continual acquisition of telemetry BP and HR. We assessed renal function by measuring urinary excretion of creatinine, sodium and potassium. Expression of sodium transporters was assessed by Western blot. Prior to OVX, baseline BP was elevated in Eln +/- mice (WT: 114 ± 3 vs. Eln +/- : 128 ± 8 mmHg; p =0.08). This was accompanied by a marked decrease in sodium/chloride co-transporter activity (phospho-NCC) and total-NCC in Eln +/- kidneys and a trend towards increased expression of epithelial sodium channel (ENaC)-alpha and beta isoforms, and decreased trend in overnight urinary sodium excretion rate (WT: 579 ± 95 vs. Eln +/- : 439 ± 82 μmol/h/g KW). Four weeks after OVX, BP was further elevated in Eln +/- mice (WT: 119 ± 7 vs. Eln +/- : 151 ± 10 mmHg; p <0.01) but was not further elevated by chronic high-salt diet (OVX + NS Eln +/- : 151 ± 10 vs. OVX + HS Eln +/- : 131 ± 5 mmHg; p =0.12). OVX also caused a robust increase in ENaC expression in Eln +/- kidneys, whereas the same effect was seen in WT kidneys only after OVX plus high salt diet. We conclude that ovarian hormones suppress blood pressure elevation attributed to Eln haploinsufficiency and protect against blood pressure sensitivity to increased dietary sodium consumption.