title: Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide.
abstract: The peptide hormone relaxin is a potent vasodilator with therapeutic potential in diseases complicated by vasoconstriction, including heart failure. However, the molecular mediators and magnitude of vasodilation may vary according to duration of exposure and artery type. The objective of these studies was to determine mechanisms of rapid (within minutes) relaxin-induced vasodilation and to examine whether relaxin dilates arteries from different animal species and vascular beds. Rat and mouse small renal, rat mesenteric, and human sc arteries were isolated, mounted in a pressure arteriograph, and treated with recombinant human relaxin (rhRLX; 1-100 ng/ml) after preconstriction with phenylephrine. Rat and mouse small renal as well as human sc arteries dilated in response to rhRLX, whereas rat mesenteric arteries did not. Endothelial removal or pretreatment with l-N(G)-monomethyl arginine (L-NMMA) abolished rapid relaxin-induced vasodilation; phosphatidylinositol-3-kinase (PI3K) inhibitors also prevented it. In cultured human endothelial cells, rhRLX stimulated nitric oxide (assessed using 4-amino-5-methylamino-2'7'-difluorofluorescein) as well as Akt and endothelial NO synthase (eNOS) phosphorylation by Western blotting but not increases in intracellular calcium (evaluated by fura-2). NO production was attenuated by inhibition of Gα(i/o) and Akt (using pertussis toxin and the allosteric inhibitor MK-2206, respectively), PI3K, and NOS. Finally, the dilatory effect of rhRLX in rat small renal arteries was unexpectedly potentiated, rather than inhibited, by pretreatment with the vascular endothelial growth factor receptor inhibitor SU5416. We conclude that relaxin rapidly dilates select arteries across a range of species. The mechanism appears to involve endothelial Gα(i/o) protein coupling to PI3K, Akt, and eNOS but not vascular endothelial growth factor receptor transactivation or increased calcium.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida 32610, USA. jtmcguane@ufl.edu
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: McGuane
authors.forename: Julianna E
authors.initials: JE
authors.lastname: Debrah
authors.forename: Laura
authors.initials: L
authors.lastname: Sautina
authors.forename: Yagna P R
authors.initials: YP
authors.lastname: Jarajapu
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Novak
authors.forename: J Peter
authors.initials: JP
authors.lastname: Rubin
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.forename: Mark
authors.initials: M
authors.lastname: Segal
authors.forename: Kirk P
authors.initials: KP
authors.lastname: Conrad
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009928:Organ Specificity; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D020318:Rats, Long-Evans; D011994:Recombinant Proteins / Q000378:metabolism; D012065:Relaxin / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D040521:Subcutaneous Tissue / Q000098:blood supply*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011994:Recombinant Proteins; D009569:Nitric Oxide; D012065:Relaxin; D058539:Phosphatidylinositol 3-Kinase