Relaxin Induces Rapid Dilation of Rodent Small Renal and Human Subcutaneous Arteries via PI3 Kinase and Nitric Oxide
| Autor: | Kirk P. Conrad, Jonathan T. McGuane, Maria B. Grant, J. Peter Rubin, Jacqueline Novak, Yagna P. R. Jarajapu, Julianna E. Debrah, Mark S. Segal, Laura Sautina |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male medicine.medical_specialty Endothelium Angiogenesis Inhibitors Vasodilation In Vitro Techniques Kidney Nitric Oxide Muscle Smooth Vascular Mice Subcutaneous Tissue Endocrinology Species Specificity Serelaxin Internal medicine medicine Animals Humans Rats Long-Evans Enzyme Inhibitors Mesenteric arteries Cells Cultured Phosphoinositide-3 Kinase Inhibitors Relaxin biology Renal-Cardiac-Vascular Middle Aged Recombinant Proteins Mesenteric Arteries Rats Mice Inbred C57BL Nitric oxide synthase medicine.anatomical_structure Organ Specificity Circulatory system biology.protein Female Endothelium Vascular Phosphatidylinositol 3-Kinase medicine.symptom Vasoconstriction Signal Transduction |
| Zdroj: | Endocrinology. 152:2786-2796 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2010-1126 |
| Popis: | 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-NG-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 Gαi/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 Gαi/o protein coupling to PI3K, Akt, and eNOS but not vascular endothelial growth factor receptor transactivation or increased calcium. |
| Databáze: | OpenAIRE |
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