Regulation of arterial reactivity by concurrent signaling through the E-prostanoid receptor 3 and angiotensin receptor 1.
Prostaglandin E2 (PGE2), a cyclooxygenase metabolite that generally acts as a systemic vasodepressor, has been shown to have vasopressor effects under certain physiologic conditions. Previous studies have demonstrated that PGE2 receptor signaling modulates angiotensin II (Ang II)-induced hypertension, but the interaction of these two systems in the regulation of vascular reactivity is incompletely characterized. We hypothesized that Ang II, a principal effector of the renin-angiotensin-aldosterone system, potentiates PGE2-mediated vasoconstriction. Here we demonstrate that pre-treatment of arterial rings with 1nM Ang II potentiated PGE2-evoked constriction in a concentration dependent manner (AUC-Ang II 2.778±2.091, AUC+Ang II 22.830±8.560, ***P<0.001). Using genetic deletion models and pharmacological antagonists, we demonstrate that this potentiation effect is mediated via concurrent signaling between the angiotensin II receptor 1 (AT1) and the PGE2 E-prostanoid receptor 3 (EP3) in the mouse femoral artery. EP3 receptor-mediated vasoconstriction is shown to be dependent on extracellular calcium in combination with proline-rich tyrosine kinase 2 (Pyk2) and Rho-kinase. Thus, our findings reveal a novel mechanism through which Ang II and PGE2 regulate peripheral vascular reactivity.
Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, United States. Electronic address: maria.c.palazzo@vanderbilt.edu.
Maria P
MP
Kraemer
Department of Pediatrics, Division of Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
Hyehun
H
Choi
Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, TN, United States.
Jeff
J
Reese
Department of Pediatrics, Division of Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
Fred S
FS
Lamb
Department of Medicine, Veterans Affairs Hospital, Nashville, TN, United States; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, United States.
Richard M
RM
Breyer
D000804:Angiotensin II / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005263:Femoral Artery / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism*; D014661:Vasoconstriction / Q000502:physiology; D054460:rho-Associated Kinases / Q000378:metabolism
D044140:Receptor, Angiotensin, Type 1; D058308:Receptors, Prostaglandin E, EP3 Subtype; D000804:Angiotensin II; D051418:Focal Adhesion Kinase 2; D054460:rho-Associated Kinases; D015232:Dinoprostone; D002118:Calcium
AT1 receptor; Angiotensin II; EP3 receptor; Prostaglandin E(2); Pyk2; Vascular reactivity