Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide

Jonathan T. McGuane, Julianna E. Debrah, Laura Sautina, Yagna P.R. Jarajapu, Jacqueline Novak, J. Peter Rubin, Maria B. Grant, Mark Segal, Kirk P. Conrad

Research output: Contribution to journalArticle

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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-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.

Original languageEnglish (US)
Pages (from-to)2786-2796
Number of pages11
JournalEndocrinology
Volume152
Issue number7
DOIs
StatePublished - Jul 1 2011

Fingerprint

Relaxin
Phosphatidylinositol 3-Kinases
Phosphatidylinositol 3-Kinase
Dilatation
Rodentia
Nitric Oxide
Arteries
Kidney
Vasodilation
Vascular Endothelial Growth Factor Receptor
Nitric Oxide Synthase
Calcium
omega-N-Methylarginine
Mesenteric Arteries
Peptide Hormones
Fura-2
Pertussis Toxin
Phenylephrine
Renal Artery
Vasoconstriction

ASJC Scopus subject areas

  • Endocrinology

Cite this

McGuane, J. T., Debrah, J. E., Sautina, L., Jarajapu, Y. P. R., Novak, J., Rubin, J. P., ... Conrad, K. P. (2011). Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinology, 152(7), 2786-2796. https://doi.org/10.1210/en.2010-1126

Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. / McGuane, Jonathan T.; Debrah, Julianna E.; Sautina, Laura; Jarajapu, Yagna P.R.; Novak, Jacqueline; Rubin, J. Peter; Grant, Maria B.; Segal, Mark; Conrad, Kirk P.

In: Endocrinology, Vol. 152, No. 7, 01.07.2011, p. 2786-2796.

Research output: Contribution to journalArticle

McGuane, JT, Debrah, JE, Sautina, L, Jarajapu, YPR, Novak, J, Rubin, JP, Grant, MB, Segal, M & Conrad, KP 2011, 'Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide', Endocrinology, vol. 152, no. 7, pp. 2786-2796. https://doi.org/10.1210/en.2010-1126
McGuane, Jonathan T. ; Debrah, Julianna E. ; Sautina, Laura ; Jarajapu, Yagna P.R. ; Novak, Jacqueline ; Rubin, J. Peter ; Grant, Maria B. ; Segal, Mark ; Conrad, Kirk P. / Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. In: Endocrinology. 2011 ; Vol. 152, No. 7. pp. 2786-2796.
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