The aging process is associated with marked sexual dimorphism in the incidence of human cardiovascular diseases, but it is unclear why the male cardiovascular system appears to """"""""age"""""""" more rapidly and often develops disease more frequently than the female system. It is clear that gonadal steroid hormones influence cardiovascular function, but the molecular basis of these effects is largely unknown, particularly for the male steroid hormones, the androgens. The long-term goal of the applicants is to elucidate the humoral mechanisms important in the regulation of vascular function and blood pressure in normotension (NT) and during the development of hypertension (HT). This proposal is based upon recent findings by the PI and others that: acute injections of testosterone (TES) reduce angina pectoris and increase coronary blood flow in men;TES produces rapid, dose-dependent vasodilation of systemic and coronary vasculatures in NT as well as HT animals;vasodilation by TES is endothelium-, sex-, and intracellular androgen receptor-independent;and TES-induced vasodilation is a structurally-specific effect of the androgen molecule on vascular smooth muscle (VSM). The objectives of this research are to elucidate the cellular and molecular mechanisms underlying TES-induced vasodilation of mesenteric arteriolar (microvascular) VSM, and to quantify the effects of HT on the cellular and molecular mechanisms of TES- induced vasodilation.
The specific aims of the proposed research are to: 1) Elucidate the mechanisms of TES-induced vasodilation in NT and during development of HT;2) Quantify the importance of single K+ channel function in TES-induced vasodilation in NT and HT;3) Quantify the role of the NO-cGMP signal transduction pathway in TES-induced vasodilation in NT and HT;4) Elucidate the structure-function relationship of the androgen molecule and its interaction with VSM cell membrane K+ channels in TES- induced vasodilation;and 5) Determine interactions between the acute (nongenomic) and long-term (genomic) mechanisms of TES action in the regulation of TES-induced vasodilation in NT and HT. This multifaceted proposal will provide a unique examination, in detail, of the cellular and molecular mechanisms underlying androgen-induced vasodilation of the peripheral microvasculature and the role of androgens in the acute regulation of vascular tone in NT and HT. It is well-established that marked sexual dimorphism exists in a variety of human cardiovascular diseases;thus the proposed research is directly relevant to human health and cardiovascular disease.
|Perusquía, Mercedes; Greenway, Clayton D; Perkins, Lisa M et al. (2015) Systemic hypotensive effects of testosterone are androgen structure-specific and neuronal nitric oxide synthase-dependent. Am J Physiol Regul Integr Comp Physiol 309:R189-95|
|Puttabyatappa, Yashoda; Stallone, John N; Ergul, Adviye et al. (2013) Peroxynitrite mediates testosterone-induced vasodilation of microvascular resistance vessels. J Pharmacol Exp Ther 345:7-14|
|Deenadayalu, Viju; Puttabyatappa, Yashoda; Liu, Alexander T et al. (2012) Testosterone-induced relaxation of coronary arteries: activation of BKCa channels via the cGMP-dependent protein kinase. Am J Physiol Heart Circ Physiol 302:H115-23|
|Perusquia, Mercedes; Espinoza, Julia; Montano, Luis M et al. (2012) Regional differences in the vasorelaxing effects of testosterone and its 5-reduced metabolites in the canine vasculature. Vascul Pharmacol 56:176-82|
|Yu, Xuan; Ma, Handong; Barman, Scott A et al. (2011) Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle. Am J Physiol Endocrinol Metab 301:E882-8|
|Perusquia, Mercedes; Stallone, John N (2010) Do androgens play a beneficial role in the regulation of vascular tone? Nongenomic vascular effects of testosterone metabolites. Am J Physiol Heart Circ Physiol 298:H1301-7|
|Han, Guichun; Ma, Handong; Chintala, Rajesh et al. (2009) Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle. J Pharmacol Exp Ther 329:850-5|
|Han, Guichun; Ma, Handong; Chintala, Rajesh et al. (2007) Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling. Am J Physiol Heart Circ Physiol 293:H314-21|