CaMK4 is a downstream effector of the α T-type calcium channel to determine the angiogenic potential of pulmonary microvascular endothelial cells.

Pulmonary microvascular endothelial cells (PMVECs) uniquely express an α-subtype of voltage-gated T-type Ca channel. We have previously revealed that the α channel functions as a background Ca entry pathway that is critical for the cell proliferation, migration, and angiogenic potential of PMVECs, a novel function attributed to the coupling between α-mediated Ca entry and constitutive Akt phosphorylation and activation. Despite this significance, mechanism(s) that link the α-mediated Ca entry to Akt phosphorylation remain incompletely understood. In this study, we demonstrate that Ca/calmodulin-dependent protein kinase (CaMK) 4 serves as a downstream effector of the α-mediated Ca entry to promote the angiogenic potential of PMVECs. Notably, CaMK2 and CaMK4 are both expressed in PMVECs. Pharmacological blockade or genetic knockdown of the α channel led to a significant reduction in the phosphorylation level of CaMK4 but not the phosphorylation level of CaMK2. Pharmacological inhibition as well as genetic knockdown of CaMK4 significantly decreased cell proliferation, migration, and network formation capacity in PMVECs. However, CaMK4 inhibition or knockdown did not alter Akt phosphorylation status in PMVECs, indicating that α/Ca/CaMK4 is independent of the α/Ca/Akt pathway in sustaining the cells' angiogenic potential. Altogether, these findings suggest a novel α-CaMK4 signaling complex that regulates the Ca-dominated angiogenic potential in PMVECs.