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Angiotensin IV-mediated pulmonary artery vasorelaxation is due to endothelial intracellular calcium release
1Department of Medicine, University of Florida College of Medicine, Gainesville, Florida 32608, USA.
Insights
Angiotensin IV triggers vasodilation in pulmonary arteries by acting on endothelial cells, not smooth muscle cells. This process involves calcium release and specific signaling pathways, highlighting its endothelium-dependent nature.
Area of Science:
- Cardiovascular Physiology
- Endothelial Cell Biology
- Vascular Pharmacology
Background:
- Pulmonary artery (PA) smooth muscle cells (PASMCs) and endothelial cells (PAECs) play critical roles in regulating vascular tone.
- Angiotensin (ANG) IV is a peptide with known roles in the cardiovascular system, but its specific mechanisms in pulmonary arteries require elucidation.
- Understanding the signaling pathways involved in ANG IV-mediated vascular effects is crucial for potential therapeutic interventions.
Purpose of the Study:
- To investigate the role of Angiotensin IV in regulating pulmonary artery vasodilation.
- To determine the specific cell types and signaling mechanisms involved in ANG IV's vascular effects.
- To elucidate the contribution of intracellular calcium ([Ca(2+)](i)) release and associated pathways in ANG IV-mediated responses.
Main Methods:
- Measurement of cyclic guanosine monophosphate (cGMP) production in PAECs and PASMCs following ANG IV stimulation.
- Assessment of ANG IV-induced vasodilation in endothelium-intact and endothelium-denuded pulmonary arteries using pharmacological agents and antagonists.
- Investigation of intracellular calcium ([Ca(2+)](i)) dynamics in PAECs using inhibitors of G protein, phospholipase C, and phosphoinositide 3-kinase (PI 3-kinase).
Main Results:
- ANG IV significantly increased cGMP production in PASMCs, mediated by PAECs, not directly in PASMCs.
- ANG IV induced dose-dependent vasodilation in intact pulmonary arteries, blocked by ANG IV receptor antagonists, indicating an endothelium-dependent mechanism.
- ANG IV-mediated [Ca(2+)](i) release in PAECs involved G protein-coupled receptors, phospholipase C, PI 3-kinase, and ryanodine-sensitive stores, crucial for vasodilation.
Conclusions:
- Angiotensin IV-mediated vasodilation of pulmonary arteries is an endothelium-dependent process.
- The signaling cascade involves ANG IV receptor activation on PAECs, leading to [Ca(2+)](i) release via G protein-phospholipase C-PI 3-kinase pathways.
- These findings reveal a novel mechanism of ANG IV action in the pulmonary vasculature, distinct from direct effects on smooth muscle cells.
Abstract:
Angiotensin (ANG) IV stimulation of pulmonary artery (PA) endothelial cells (PAECs) but not of PA smooth muscle cells (PASMCs) resulted in significant increased production of cGMP in PASMCs. ANG IV receptors are not present in PASMCs, and PASMC nitric oxide synthase activity was not altered by ANG IV. ANG IV caused a dose-dependent vasodilation of U-46619-precontracted endothelium-intact but not endothelium-denuded PAs, and this response was blocked by the ANG IV receptor antagonist divalinal ANG IV but not by ANG II type 1 and 2 receptor blockers. ANG IV receptor-mediated increased intracellular Ca(2+) concentration ([Ca(2+)](i)) release from intracellular stores in PAECs was blocked by divalinal ANG IV as well as by the G protein, phospholipase C, and phosphoinositide (PI) 3-kinase inhibitors guanosine 5'-O-(2-thiodiphosphate), U-73122, and LY-294002, respectively, and was regulated by both PI 3-kinase- and ryanodine-sensitive Ca(2+) stores. Basal and ANG IV-mediated vasorelaxation of endothelium-denuded PAs was restored by exogenous PAECs but not by exogenous PAECs pretreated with the intracellular Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM. These results demonstrate that ANG IV-mediated vasodilation of PAs is endothelium dependent and regulated by [Ca(2+)](i) release through receptor-coupled G protein-phospholipase C-PI 3-kinase signaling mechanisms.