title: 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 3 hours in vitro attenuated myogenic constriction, which was blocked by inhibitors of gelatinases, the endothelin B receptor, and NO 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 the study of human arteries. Incubation of small human subcutaneous arteries with relaxin for 3 hours in vitro also attenuated myogenic constriction through the same molecular intermediates. Vascular endothelial growth factor receptor inhibitor SU5416, 3 different vascular endothelial growth factor, and 2 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 matrix metalloproteinase 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.
authors.affiliation: Department of Physiology and Functional Genomics and D H Barron Reproductive and Perinatal Biology Research Program, University of Florida College of Medicine, 1600 SW Archer Rd, M552, PO Box 100274, Gainesville, FL 32610-0274, USA. jtmcguane@ufl.edu
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: McGuane
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Danielson
authors.forename: Julianna E
authors.initials: JE
authors.lastname: Debrah
authors.forename: J Peter
authors.initials: JP
authors.lastname: Rubin
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Novak
authors.forename: Kirk P
authors.initials: KP
authors.lastname: Conrad
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology; D065131:Endothelin B Receptor Antagonists; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D011247:Pregnancy; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D044023:Receptor, Endothelin B / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012065:Relaxin / Q000235:genetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D004151:Dipeptides; D065131:Endothelin B Receptor Antagonists; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010456:Peptides, Cyclic; D011758:Pyrroles; D044023:Receptor, Endothelin B; D011994:Recombinant Proteins; C087120:RES 701-1; D019323:omega-N-Methylarginine; C116890:Semaxinib; D012065:Relaxin; D019001:Nitric Oxide Synthase; D040262:Receptors, Vascular Endothelial Growth Factor; D020778:Matrix Metalloproteinase 2