Protein Kinase CK2 Regulates Nerve/Glial Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes

Abstract

Protein kinase CK2 is a crucial regulator of endothelial cell proliferation, migration and sprouting during angiogenesis. However, it is still unknown whether this kinase additionally affects the angiogenic activity of other vessel-associated cells. In this study, we investigated the effect of CK2 inhibition on primary human pericytes. We found that CK2 inhibition reduces the expression of nerve/glial antigen (NG)2, a crucial factor which is involved in angiogenic processes. Reporter gene assays revealed a 114 bp transcriptional active region of the human NG2 promoter, whose activity was decreased after CK2 inhibition. Functional analyses demonstrated that the pharmacological inhibition of CK2 by CX-4945 suppresses pericyte proliferation, migration, spheroid sprouting and the stabilization of endothelial tubes. Moreover, aortic rings of NG2−/− mice showed a significantly reduced vascular sprouting when compared to rings of NG2+/+ mice, indicating that NG2 is an important regulator of the angiogenic activity of pericytes. In vivo, implanted Matrigel plugs containing CX-4945-treated pericytes exhibited a lower microvessel density when compared to controls. These findings demonstrate that CK2 regulates the angiogenic activity of pericytes through NG2 gene expression. Hence, the inhibition of CK2 represents a promising anti-angiogenic strategy, because it does not only target endothelial cells, but also vessel-associated pericytes.

CK2 Activity Mediates the Aggressive Molecular Signature of Glioblastoma Multiforme by Inducing Nerve/Glial Antigen (NG)2 Expression

“…Recently, we have identified a 114-bp fragment (NG2 p1.2.4.1 ) close to the NG2 start codon as a CK2-dependent active promoter region in human pericytes [ 19 ]. Therefore, we investigated whether the activity of NG2 p1.2.4.1 is also affected by CK2 inhibition in GBM cells.…”

“…This indicates that NG2 is not only involved in tumor cell proliferation but also in angiogenesis. We previously found that CK2 inhibition reduces the NG2-dependent angiogenic activity of human pericytes [ 19 ]. Therefore, we suggest that CX-4945 is a promising compound for the treatment of NG2-positive GBM, because it targets both the vascular and tumor compartment.…”

“…This, in turn, activates cell proliferation, cell motility, inflammation and angiogenesis [ 15 , 16 , 17 , 18 ]. Recently, we have identified CK2 as a novel regulator of NG2-dependent signaling pathways [ 19 ]. Our results revealed that inhibition of CK2 suppresses NG2 expression in pericytes, which reduces their angiogenic activity [ 19 ].…”

“…Recently, we have identified CK2 as a novel regulator of NG2-dependent signaling pathways [ 19 ]. Our results revealed that inhibition of CK2 suppresses NG2 expression in pericytes, which reduces their angiogenic activity [ 19 ].…”

Andrographolide Promotes Interaction Between Endothelin-Dependent EDNRA/EDNRB and Myocardin-SRF to Regulate Pathological Vascular Remodeling

“…The spheroid sprouting assay was performed as described previously ( 33 ). The methylcellulose solution was prepared by dissolving 6 g of methylcellulose (sigma) into 250 ml of prewarmed serum free medium, and 250 ml of DMEM containing 10% serum was added.…”