Endogenous Relaxin Regulates Vascular Function in Nonpregnant Females and Males

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DESCRIPTION (provided by applicant): Although traditionally associated with function of reproductive organs during pregnancy, relaxin (Rlx) is emerging as an important player in vascular function. We previously showed that circulating Rlx whether endogenously released during pregnancy or exogenously adminstered to conscious, nonpregnant female and male rats induces systemic and renal vasodilation, and increases arterial compliance. Here, we propose to explore two overarching concepts: (1) endogenous Rlx regulates vascular function in nonpregnant females and males, and (2) there is a local, vascular-derived Rlx hormone/receptor system. These concepts are supported by preliminary molecular analyses showing Rlx and Rlx receptor expression by isolated rodent arteries and cultured human vascular cells, as well as by functional studies demonstrating reduced compliance and increased myogenic reactivity of arteries isolated from nonpregnant female and male mice deficient in the M1 relaxin gene. We have designed five Hypotheses and Specific Aims to test these two overarching concepts. In Aims 1 and 2, we propose to corroborate and extend our preliminary studies by further characterizing the expression of relaxins and relaxin receptors in vascular tissues from mice and humans. In Aims 3-5, we propose to investigate steady and pulsatile systemic arterial loads, and renal hemodynamics in conscious and unrestrained, chronically instrumented wild-type and Rlx-deficient mice, as well as myogenic reactivity and passive mechanics of arteries isolated from these animals. These studies will utilize nonpregnant female and male mice, as well as both young and older animals, thereby exploring gender and age interactions. To our knowledge, the concepts of endogenous Rlx mediating vascular relaxation and increased compliance in nonpregnant females and males, and of a local, vascular-derived Rlx hormone/receptor system are novel. If they are validated, then abnormalities in endogenous Rlx or its receptor may contribute to various vascular pathologies, e.g., a deficiency might contribute to increased arterial constriction and stiffness associated with hypertension and aging (both normal and accelerated), and an excess might contribute to aortic aneurysm formation and dissection. Thus, the influence of endogenous Rlx on vascular function is likely to be a general phenomenon, and not one limited exclusively to pregnancy.