scholarly journals Relaxin Induces Rapid Dilation of Rodent Small Renal and Human Subcutaneous Arteries via PI3 Kinase and Nitric Oxide

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2786-2796 ◽  
Author(s):  
Jonathan T. McGuane ◽  
Julianna E. Debrah ◽  
Laura Sautina ◽  
Yagna P. R. Jarajapu ◽  
Jacqueline Novak ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Peptide Hormone ◽  
Mesenteric Arteries ◽  
No Production ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

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.

Abstract MP10: Early Functional and Structural Alterations of Resistance Arteries in Mice Treated with an Inhibitor of the Vascular Endothelial Growth Factor Receptor

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
CARMINE SAVOIA ◽  
Emanuele Arrabito ◽  
Augusto C Montezano ◽  
Carmine Nicoletti ◽  
Heather Y Small ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Remodeling ◽  
Growth Factor Receptor ◽  
Mesenteric Arteries ◽  
No Production ◽  
Vascular Endothelial ◽  
Resistance Arteries ◽  
Structural Alterations ◽  
Endothelial Growth Factor

Background: Inhibition of tyrosine kinases receptors such as vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) improves outcomes in patients with cancers. Only VEGFR inhibitors, however, induce severe hypertension whose mechanisms remain unclear. We hypothesized that VEGFR inhibitors may induce early vascular functional and structural alterations, that may precede the development of hypertension. Methods and results: Normotensive SV-129 mice (8 weeks old, 5 for each group) were treated or not with the VEGFR inhibitor Vatalanib (VAT, 100 mg/Kg/day) or the EGFR inhibitor Gefitinib (GEF, 100 mg/Kg/day). Vehicle-treated control mice were also studied. Blood pressure (BP) was measured by tail-cuff method. Endothelium-dependent and -independent relaxations were assessed by concentration-response curves to acetylcholine (1 nM to 100 μM) ± L-NAME (100 μM) and sodium nitroprusside (10 nM to 1 mM) respectively, in mesenteric arteries pre-contracted with norepinephrine (10 μM). Media-to-lumen ratio (M/L, an index of early vascular remodeling), and cross sectional area (CSA) were evaluated on pressurized preparations. After two weeks, BP was similarly preserved in both VAT- and GEF-treated mice as compared to vehicle-treated mice (89.8±1.5 mmHg and 87.2±2.8 mmHg vs 92.2±2.2 mmHg, respectively, NS). Endothelium-dependent relaxation was similarly preserved in vehicle-treated and GEF-treated mice, whereas it was reduced in VAT-treated mice (-17% vs vehicle-treated mice, P<0.05). L-NAME blunted acetylcholine-induced relaxation in all groups except in VAT-treated mice, suggesting an impairment of NO production only in this group. Endothelium-independent relaxation was similar in all groups. Only VAT-treated mice presented increased M/L as compared to vehicle-treated mice (6.3±0.1% vs 5.4±0.1%, P<0.05). M/L resulted similar in GEF-treated and vehicle-treated mice. CSA was similar in all groups. Conclusion: In normotensive mice, only VAT promoted early vascular alterations such as endothelial dysfunction and vascular remodeling in resistance arteries. Those changes in the vasculature are distinctive of hypertension and might precede and sustain the development of the hypertensive disease.

scholarly journals Vascular Endothelial Growth Factor Receptor 2 Controls Blood Pressure by Regulating Nitric Oxide Synthase Expression

Hypertension ◽  
2009 ◽  
Vol 54 (3) ◽  
pp. 652-658 ◽  
Author(s):  
Carie S. Facemire ◽  
Andrew B. Nixon ◽  
Robert Griffiths ◽  
Herbert Hurwitz ◽  
Thomas M. Coffman
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Nitric Oxide Synthase ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Oxide Synthase ◽  
Endothelial Growth Factor

scholarly journals Novel human Ab against vascular endothelial growth factor receptor 2 shows therapeutic potential for leukemia and prostate cancer

2019 ◽  
Vol 110 (12) ◽  
pp. 3773-3787 ◽  
Author(s):  
Ruei‐Min Lu ◽  
Chiung‐Yi Chiu ◽  
I‐Ju Liu ◽  
Yu‐Ling Chang ◽  
Yaw‐Jen Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

scholarly journals Vascular Endothelial Growth Factor Receptor-1 Modulates Vascular Endothelial Growth Factor-Mediated Angiogenesis via Nitric Oxide

2001 ◽  
Vol 159 (3) ◽  
pp. 993-1008 ◽  
Author(s):  
Benedetta Bussolati ◽  
Caroline Dunk ◽  
Malcolm Grohman ◽  
Christopher D. Kontos ◽  
Justin Mason ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

scholarly journals Direct Evidence for Endothelial Vascular Endothelial Growth Factor Receptor-1 Function in Nitric Oxide–Mediated Angiogenesis

2006 ◽  
Vol 99 (7) ◽  
pp. 715-722 ◽  
Author(s):  
Shakil Ahmad ◽  
Peter W. Hewett ◽  
Ping Wang ◽  
Bahjat Al-Ani ◽  
Melissa Cudmore ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Direct Evidence ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor
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