α1G T-type calcium channel determines the angiogenic potential of pulmonary microvascular endothelial cells

Author:

Zheng Zhen1,Chen Hairu1,Xie Peilin1,Dickerson Carol A.2,King Judy A. C.3,Alexeyev Mikhail F.4,Wu Songwei1

Affiliation:

1. Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama

2. Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia

3. Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana

4. Center for Lung Biology and Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama

Abstract

Pulmonary microvascular endothelial cells (PMVECs) display a rapid angioproliferative phenotype, essential for maintaining homeostasis in steady-state and promoting vascular repair after injury. Although it has long been established that endothelial cytosolic Ca2+ ([Ca2+]i) transients are required for proliferation and angiogenesis, mechanisms underlying such regulation and the transmembrane channels mediating the relevant [Ca2+]i transients remain incompletely understood. In the present study, the functional role of the microvascular endothelial site-specific α1G T-type Ca2+ channel in angiogenesis was examined. PMVECs intrinsically possess an in vitro angiogenic “network formation” capacity. Depleting extracellular Ca2+ abolishes network formation, whereas blockade of vascular endothelial growth factor receptor or nitric oxide synthase has little or no effect, suggesting that the network formation is a [Ca2+]i-dependent process. Blockade of the T-type Ca2+ channel or silencing of α1G, the only voltage-gated Ca2+ channel subtype expressed in PMVECs, disrupts network formation. In contrast, blockade of canonical transient receptor potential (TRP) isoform 4 or TRP vanilloid 4, two other Ca2+ permeable channels expressed in PMVECs, has no effect on network formation. T-type Ca2+ channel blockade also reduces proliferation, cell-matrix adhesion, and migration, three major components of angiogenesis in PMVECs. An in vivo study demonstrated that the mice lacking α1G exhibited a profoundly impaired postinjury cell proliferation in the lungs following lipopolysaccharide challenge. Mechanistically, T-type Ca2+ channel blockade reduces Akt phosphorylation in a dose-dependent manner. Blockade of Akt or its upstream activator, phosphatidylinositol-3-kinase (PI3K), also impairs network formation. Altogether, these findings suggest a novel functional role for the α1G T-type Ca2+ channel to promote the cell’s angiogenic potential via a PI3K-Akt signaling pathway.

Funder

HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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