Emerging role of relaxin in renal and cardiovascular function

Abstract

Conrad, Kirk P., and Jacqueline Novak. Emerging role of relaxin in renal and cardiovascular function. Am J Physiol Regul Integr Comp Physiol 287: R250 -R261, 2004; 10.1152/ajpregu.00672.2003.-Although traditionally associated with reproductive processes, relaxin is emerging as an important player in renal and cardiovascular function. Much of our recently acquired understanding of relaxin in this new context has arisen from studies of maternal renal and cardiovascular adaptations to pregnancy in rats where the hormone is turning out to be an important mediator. First, we highlight the influence of relaxin on renal hemodynamics and glomerular filtration rate, as well as on other peripheral circulations. Second, we discuss the effect of relaxin on both the steady and pulsatile systemic arterial load, as well as on the heart, in particular, coronary blood flow. Third, we consider the impact of the hormone on cultured endothelial and vascular smooth muscle cells. Fourth, we address the interaction of relaxin with renal and cardiac disease, as well as its role in angiogenesis. Finally, in Perspectives, we point out several key research questions in need of investigation that relate to a potential autocrine/paracrine role of relaxin in renal and cardiovascular tissues. Furthermore, on the basis of its potent vasodilatory and matrix-degrading attributes, we speculate about the therapeutic potential of relaxin in renal and cardiovascular diseases. pregnancy; kidney circulation; glomerular filtration; osmoregulation; peripheral circulation; systemic hemodynamics; vasodilation; arterial compliance; heart; myogenic reactivity; angiogenesis; relaxin receptors; matrix metalloproteinase; gelatinase; endothelin B receptor; nitric oxide; angiotensin II THE OBJECTIVE OF THIS REVIEW is to highlight the new and emerging roles of relaxin (RLX) in the renal and cardiovascular systems. Traditionally, RLX has been tied to reproductive processes during pregnancy, because most investigations conducted by reproductive biologists have dealt with the hormone in this context. The traditional sources of RLX have been reproductive tissues such as the corpus luteum of the ovary from which the hormone emanates and circulates during the luteal phase of the menstrual cycle and during pregnancy in women (95). Furthermore, there has been no well-established role in the male. However, the concept of a role for RLX in cardiovascular function actually has its antecedents early on in the history of RLX research, when Frederick L. Hisaw, who discovered the hormone (47, 113), noted that after administration of RLX to castrated monkeys, there were marked morphological changes in the endothelial cells of the endometrium consistent with hypertrophy and hyperplasia (48). The concept that RLX can affect blood vessel structure and function has since gained considerable support, particularly in the last decade. Much of our recently gained knowledge of RLX in this new light has arisen from studies of maternal renal and cardiovascular function in the gravid rat mo...

Cerebral blood flow is increased during controlled ovarian stimulation

“…VEGF was reported to increase local CBF in a rat model (38). Relaxin is a second factor that was reported to affect renal and cardiovascular hemodynamics (6) and is secreted by the stimulated ovaries during the luteal phase (17). Those factors, and possibly others, may act in concert with estrogen to promote increase in CBF during the luteal phase.…”

Influence of Recombinant Human Relaxin on Renal Hemodynamics in Healthy Volunteers

“…Because RLX is a functional AngII antagonist in the vasculature (16,19), perhaps it also antagonizes AngII-induced secretion of aldosterone or the influence of AngII on renal tubular sodium absorption. Moreover, RLX has been shown to exert its renal vasodilatory influence ultimately through ET and ET B stimulation of NO production (6,15,16,26). Conceivably, RLX may influence sodium reabsorption and potassium secretion in the collecting duct through ET activation of ET B receptors, thereby inhibiting Na ϩ -K ϩ -ATPase activity (27 and citations therein).…”

“…Indirect evidence indicates that comparable mechanisms are operational in human pregnancy (2)(3)(4). There is comprehensive evidence that the ovarian hormone relaxin (RLX) is an essential mediator of the renal vasodilation and hyperfiltration (as well as osmoregulatory changes) in midterm pregnant rats (5), and current evidence supports a mechanism whereby RLX upregulates vascular gelatinase, matrix metalloproteinase 2, promoting cleavage of big endothelin (ET) into ET , which then causes nitric oxide (NO)-mediated vasodilation via endothelial ET B receptors (6,7). Until now, the investigation of the vasoactive properties of RLX in the human kidney has been hampered by difficulties that are encountered in pharmacologic stimulation of RLX secretion outside pregnancy (8) and by the absence of an exogenous RLX product for human administration.…”

Relaxin exerts two opposite effects on mechanical activity and nitric oxide synthase expression in the mouse colon

“…nitric oxide synthase isoforms; nitric oxide synthase splice variants; immunohistochemistry; mechanical responses RELAXIN, a 6,000 Da hormone peptide mainly produced by the corpus luteum, has been shown to exert a variety of physiological effects on the smooth muscle of reproductive and nonreproductive organs, most of which occur through a nitric oxide (NO)-mediated mechanism (1,12,17,33). The latter effects can be direct on the smooth muscle cells (SMC) or mediated by the endothelial cells (2,12,17,30,36). In the gastrointestinal tract, relaxin has been shown to cause depression of muscle contractility by modulating the activity and expression of the different nitric oxide synthase (NOS) isoforms (8,3,4,40).…”

“…These findings may help to better understand the physiology of NO in the gastrointestinal tract and the role that the "relaxin-NO" system plays in motor disorders such as functional bowel disease. nitric oxide synthase isoforms; nitric oxide synthase splice variants; immunohistochemistry; mechanical responses RELAXIN, a 6,000 Da hormone peptide mainly produced by the corpus luteum, has been shown to exert a variety of physiological effects on the smooth muscle of reproductive and nonreproductive organs, most of which occur through a nitric oxide (NO)-mediated mechanism (1,12,17,33). The latter effects can be direct on the smooth muscle cells (SMC) or mediated by the endothelial cells (2,12,17,30,36).…”