Failure to Vasodilate in Response to Salt Loading Blunts Renal Blood Flow and Causes Salt-Sensitive Hypertension.

AIMS: Salt sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension. METHODS AND RESULTS: Mice selectively expressing a PPARγ dominant negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4-week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3 days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in renal NO production which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice. CONCLUSIONS: We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular PPARγ impairment. TRANSLATIONAL PERSPECTIVE: Mutations in PPARγ cause hypertension whereas treatment with PPARγ activators lowers blood pressure. The cardioprotective role of PPARγ in blood pressure regulation are largely mediated by its actions in the vasculature, but the role of vascular PPARγ in salt sensitivity of blood pressure remains unknown. We present evidence that smooth muscle PPARγ protects from salt sensitivity by promoting renal and systemic vasodilation in response to HSD and that mutations in PPARγ prevent this compensatory mechanism. The multi-faceted roles of PPARγ signaling necessitate the design of new therapies that selectively utilize the protective effects of PPARγ in vasculature, while minimizing the potential adverse effects of global PPARγ activation by thiazolidinediones.