Causal relationship between
sodium and
hypertension has been proposed and various changes in Na+,K+-
ATPase (sodium pump) activity have been described in established
primary hypertension. A number of direct vascular effects of
estradiol have been reported, including its impact on the regulation of
sodium pump activity and vasomotor tone. The effects of
estradiol involve the activation of multiple signaling cascades, including phosphatydil inositol-3
kinase (PI3K) and p42/44
mitogen-activated protein kinase (p42/44(MAPK)). In addition, some of the effects of
estradiol have been linked to activity of cytosolic
phospholipase A(2) (cPLA(2)). One possible cardioprotective mechanism of
estradiol involves of the interaction between
estradiol and the
rennin-
angiotensin system (RAS). Elevated circulating and tissue levels of
angiotensin II (Ang II) have been implicated in the development of
hypertension and
heart failure. The aim of our investigation was to elucidate the signaling mechanisms employed by
estradiol and Ang II in mediating
sodium pump, in vascular smooth muscle cells (VSMC). The aim of our investigation was to elucidate the signaling mechanisms employed by
estradiol and Ang II in mediating
sodium pump activity/expression in VSMC, with particular emphasis on PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. Our primary hypothesis is that
estradiol stimulates
sodium pump activity/expression in VSMC via PI3K/cPLA(2)/p42/44(MAPK) dependent mechanism and, that impaired
estradiol-stimulated
sodium pump activity/expression in hypertensive rodent models (i.e. SHR), Ang II-mediated vascular impairment of
estradiol is related to a decrease ability of
estradiol to stimulate the PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. An important corollary to this hypothesis is that in hypertensive state (i.e. SHR rats) the decreasing in ACE
enzyme activity and/or AT1 receptor expression caused by administration of
estradiol is accompanying with abrogated ability of Ang II to decrease IRS-1/PI3K association, and consequent PI3K/cPLA(2)/p42/44(MAPK) activity and associated
sodium pump activity/expression. A clear characterization of how Ang II attenuates
estradiol signaling may lead to a better understanding of the molecular mechanism(s) underlying pathophysiological conditions such as
hypertension and to understanding how certain pathophysiological situations affect
sodium pump activity/expression in VSMC.