Role of ROS signaling in differential hypoxic Ca2+ and contractile responses in pulmonary and systemic vascular smooth muscle cells

Abstract

Hypoxia causes a large increase in [Ca2+]i and attendant contraction in pulmonary artery smooth muscle cells (PASMCs), but not in systemic artery SMCs. The different responses meet the respective functional needs in these two distinct vascular myocytes; however, the underlying molecular mechanisms are not well known. We and other investigators have provided extensive evidence to reveal that voltage-dependent K+ (KV) channels, canonical transient receptor potential (TRPC) channels, ryanodine receptor Ca2+ release channels (RyRs), cyclic adenosine diphosphate-ribose, FK506 binding protein 12.6, protein kinase C, NADPH oxidase and reactive oxygen species (ROS) are the essential effectors and signaling intermediates in the hypoxic increase in [Ca2+]i in PASMCs and HPV, but they may not primarily underlie the diverse cellular responses in pulmonary and systemic vascular myocytes. Hypoxia significantly increases mitochondrial ROS generation in PASMCs, which can induce intracellular Ca2+ release by opening RyRs, and may also cause extracellular Ca2+ influx by inhibiting KV channels and activating TRPC channels, leading to a large increase in [Ca2+]i in PASMCs and HPV. In contrast, hypoxia has no or a minor effect on mitochondrial ROS generation in systemic SMCs, thereby causing no change or a negligible increase in [Ca2+]i and contraction. Further preliminary work indicates that Rieske iron–sulfur protein in the mitochondrial complex III may perhaps serve as a key initial molecular determinant for the hypoxic increase in [Ca2+]i in PASMCs and HPV, suggesting its potential important role in different cellular changes to respond to hypoxic stimulation in pulmonary and systemic artery myocytes. All these findings have greatly improved our understanding of the molecular processes for the differential hypoxic Ca2+ and contractile responses in vascular SMCs from distinct pulmonary and systemic circulation systems.

Important role of PLC-γ1 in hypoxic increase in intracellular calcium in pulmonary arterial smooth muscle cells

“…Unlike in PAs, hypoxia fails to alter the activity of total PLC in mesenteric arteries. These data are consistent with the widely accepted view that hypoxia causes a large increase in [Ca 2ϩ ] i in PASMCs, but not in mesenteric and other systemic artery myocytes (29). Using Western blot analysis and immunofluorescence staining, we have found expression of PLC-␥1 protein in PAs and PASMCs (Fig.…”

O 2 sensing, mitochondria and ROS signaling: The fog is lifting

“…Other studies have led to similar conclusions 91–94 . If mitochondria release ROS to the cytosol, an oxidant signal in the mitochondrial intermembrane space should accompany the cytosolic oxidant response.…”

Hypoxia-Dependent Reactive Oxygen Species Signaling in the Pulmonary Circulation: Focus on Ion Channels

“…The best characterized pathways of Ca 2 + entry into PASMC are through VOCCs (regulated by the resting membrane potential) and TRP channels (TRPC; voltageindependent nonselective cation channels, SOCs and ROCs) (160). An increase of intracellular Ca 2 + concentration in PASMC has been widely accepted to be a critical event for HPV (151). In the pulmonary vasculature, the acute hypoxic Ca 2 + release in PASMC is dependent to a lesser degree on VOCCs (inhibition attenuated hypoxic Ca 2 + release by 30%) and to a greater degree on other transmembrane channels such as TRPC (inhibition attenuated hypoxic Ca 2 + release by 60%) (141).…”

“…The determination of the pulmonary vascular tone by ion channels in response to hypoxia is widely accepted. Whether due to an increase of decrease of ROS, Ca 2 + entry through Ltype channels, and release of calcium from the sarcoplasmic reticulum (SR) causes an increase in intracellular Ca 2 + , and initiates and maintains contraction of pulmonary vascular smooth muscle cells (VSMC) in response to hypoxia (151,158).…”