Antagonism of Endothelin Action Reverses Neurovascular Remodeling

Abstract

The development of hypertension in Stroke-prone spontaneously hypertensive rats (SHRSP) can be divided into three consecutive stages, namely prehypertensive, typical hypertensive and malignant hypertensive. Malignant hypertensive may lead to spontaneous stroke, in part, due to abnormalities in the cerebrovasculature. Here, we show an age- and hypertension stage-dependent profile of vascular endothelial growth factor (VEGF) and its receptor, Flk-1, in the frontal cortex of SHRSP rats, and upregulation in levels of endothelin (ET)-1 and its type A receptor (ETAR), compared to the genetic control, normotensive WKY rats. This molecular phenomenon was associated with reduced cerebral blood flow volume during malignant hypertension. In contrast, levels of ET type B receptor (ETBR), and those of endothelial nitric oxide synthase (eNOS) and Akt, molecules that act downstream of VEGF, were downregulated. Thus, the subsequent set of experiments were designed to investigate whether antagonism of ET-1 actions, using ETA/-B dual receptor antagonist SB209670, could restore to normal the molecular profile of these factors (ET-1, VEGF, eNOS, and Akt). Blockage of ET-1 restored to normal levels of serum and cerebral ET-1 and ETAR; VEGF and its receptor (Flk-1); eNOS and Akt, compared to age-matched WKY. We conclude that alterations in VEGF and ET-1 signaling could, in part, underlie the pathogenesis and progression of hypertension-induced vascular remodeling in the frontal cortex of SHRSP rats. Supported by Ministry of Education and Science in Japan.