Angiogenic Growth Factors Are New and Essential Players in the Sustained Relaxin Vasodilatory Pathway in Rodents and Humans

Abstract

Relaxin is emerging as an important vasodilator of pregnancy, and is being tested for afterload reduction in acute heart failure. However, the mechanisms underlying relaxin-induced vasodilation are incompletely understood. The aims of this study were to establish a new in vitro model for relaxin-induced vasodilation, and to use this approach as well as chronically instrumented, conscious rats to investigate the role of angiogenic growth factors in the relaxin vasodilatory pathway. Incubation of rat and mouse small renal arteries with recombinant human H2 relaxin for 3hr in vitro attenuated myogenic constriction, which was blocked by inhibitors of gelatinases, the endothelin B receptor and nitric oxide synthase. These findings corroborate ex vivo observations in arteries isolated from relaxin-infused nonpregnant and midterm pregnant rats, thereby validating the new experimental approach and enabling study of human arteries. Incubation of small human subcutaneous arteries with relaxin for 3hr in vitro also attenuated myogenic constriction through the same molecular intermediates. Vascular endothelial growth factor receptor inhibitor SU5416, three different vascular endothelial growth factor and two different placental growth factor neutralizing antibodies prevented relaxin from attenuating myogenic constriction in rat and mouse small renal, and human subcutaneous arteries. SU5416 administration also prevented relaxin-induced renal vasodilation and hyperfiltration in chronically instrumented, conscious rats. Small renal arteries isolated from these rats demonstrated increased MMP-2 activity in the relaxin-infused group, which was not prevented by SU5416. We conclude that there is concordance of relaxin vasodilatory mechanisms in rats, mice and humans, and angiogenic growth factors are novel and essential intermediates.

Maternal vasodilation in pregnancy: the emerging role of relaxin

“…On the one hand, the expected attenuation of myogenic constriction was not observed in small renal arteries isolated from ET B receptor-deficient rats that were either pregnant or nonpregnant and chronically administered rhRLX, thus corroborating earlier findings using the ET B receptor antagonists RES-701-1 and SB209670 (37,44,51,56,60). On the other hand, enhanced MMP-2 activity was observed in small renal arteries isolated from the same rats.…”

“…Subsequently, increased MMP-2 mRNA and protein was identified as a basis for the increased activity (43). Other reports corroborated the increased expression of arterial MMP-2 during pregnancy or relaxin administration (23,46,51,83). Unexpectedly, however, after 4 to 6 h of relaxin administration, MMP-9 activity was upregulated in small renal and mesenteric arteries, while pro and active MMP-2 were unchanged (45).…”

“…In light of the prominent role of endothelium and NO in relaxin and pregnancy vasodilatory responses, it was surprising that RXFP1 mRNA and protein were predominantly expressed in smooth muscle with barely detectable levels in endothelium (Conrad KP, unpublished observation). Based on this molecular evidence, a paracrine role for VEGF was postulated to initiate the gelatinase-ET B receptor-NO pathway in endothelium, subsequent to RXFP1 activation in vascular smooth muscle by relaxin (51). Indeed, relaxin had been reported to stimulate VEGF expression in other cell types (reviewed in Ref.…”

“…Indeed, relaxin had been reported to stimulate VEGF expression in other cell types (reviewed in Ref. 51).…”

New Developments in the Pathogenesis of Preeclampsia

“…During the course of the treatment, the extracorporeal adsorption device only lowered soluble sFlt1 levels by 30% on average, validating the idea that just partially lowering circulating sFlt1 levels is sufficient to successfully prolong preeclamptic pregnancies. Experimental studies suggest that the hormone relaxin may also be used to ameliorate preeclampsia by improving vascular compliance and upregulating VEGF locally 69 . A phase I study to test the safety of human relaxin in women with preeclampsia has recently been completed 70 .…”