| First Author | O'Brien BJ | Year | 2021 |
| Journal | FASEB J | Volume | 35 |
| Issue | 4 | Pages | e21437 |
| PubMed ID | 33749880 | Mgi Jnum | J:310378 |
| Mgi Id | MGI:6762889 | Doi | 10.1096/fj.202002755R |
| Citation | O'Brien BJ, et al. (2021) CaMKIIdelta is upregulated by pro-inflammatory cytokine IL-6 in a JAK/STAT3-dependent manner to promote angiogenesis. FASEB J 35(4):e21437 |
| abstractText | Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous serine threonine kinase with established roles in physiological and pathophysiological vascular remodeling. Based on our previous study demonstrating that CaMKIIdelta promotes thrombin-induced endothelial permeability and recent reports that CaMKII may contribute to inflammatory remodeling in the heart, we investigated CaMKIIdelta-dependent regulation of endothelial function downstream of an interleukin-6 (IL-6)/JAK/STAT3 signaling axis. Upon treatment with IL-6 and its soluble receptor (sIL-6r), CaMKIIdelta expression is significantly induced in HUVEC. Using pharmacological inhibitors of JAK and siRNA targeting STAT3, we demonstrated that activation of STAT3 is sufficient to induce CaMKIIdelta expression. Under these conditions, rather than promoting IL-6-induced permeability, we found that CaMKIIdelta promotes endothelial cell migration as measured by live cell imaging of scratch wound closure and single-cell motility analysis. In a similar manner, endothelial cell proliferation was attenuated upon knockdown of CaMKIIdelta as determined by growth curves, cell cycle analysis, and capacitance of cell-covered electrodes as measured by ECIS. Using inducible endothelial-specific STAT3 knockout mice, we demonstrate that STAT3 signaling promotes developmental angiogenesis in the neonatal mouse retina assessed at postnatal day 6. CaMKIIdelta expression in retinal endothelium was attenuated in these animals as measured by qPCR. STAT3's effects on angiogenesis were phenocopied by the endothelial-specific knockout of CaMKIIdelta, with significantly reduced vascular outgrowth and number of junctions in the developing P6 retina. For the first time, we demonstrate that transcriptional regulation of CaMKIIdelta by STAT3 promotes endothelial motility, proliferation, and in vivo angiogenesis. |
