| First Author | Zheng Z | Year | 2019 |
| Journal | Am J Physiol Cell Physiol | Volume | 316 |
| Issue | 3 | Pages | C353-C364 |
| PubMed ID | 30649917 | Mgi Jnum | J:273350 |
| Mgi Id | MGI:6281083 | Doi | 10.1152/ajpcell.00336.2018 |
| Citation | Zheng Z, et al. (2019) alpha1G T-type calcium channel determines the angiogenic potential of pulmonary microvascular endothelial cells. Am J Physiol Cell Physiol 316(3):C353-C364 |
| abstractText | 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 Ca(2+) ([Ca(2+)]i) transients are required for proliferation and angiogenesis, mechanisms underlying such regulation and the transmembrane channels mediating the relevant [Ca(2+)]i transients remain incompletely understood. In the present study, the functional role of the microvascular endothelial site-specific alpha1G T-type Ca(2+) channel in angiogenesis was examined. PMVECs intrinsically possess an in vitro angiogenic "network formation" capacity. Depleting extracellular Ca(2+) 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 [Ca(2+)]i-dependent process. Blockade of the T-type Ca(2+) channel or silencing of alpha1G, the only voltage-gated Ca(2+) 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 Ca(2+) permeable channels expressed in PMVECs, has no effect on network formation. T-type Ca(2+) 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 alpha1G exhibited a profoundly impaired postinjury cell proliferation in the lungs following lipopolysaccharide challenge. Mechanistically, T-type Ca(2+) 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 alpha1G T-type Ca(2+) channel to promote the cell's angiogenic potential via a PI3K-Akt signaling pathway. |
