CaMKIIδ is upregulated by pro‐inflammatory cytokine IL‐6 in a JAK/STAT3‐dependent manner to promote angiogenesis. Issue 4 (22nd March 2021)

• Record Type: Journal Article
• Authors: O'Brien, Brendan J.; Singer, Harold A.; Adam, Alejandro P.; Ginnan, Roman G.
• Is Part Of: FASEB journal. Volume 35:Issue 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-22
• Subjects: angiogenesis -- CaMKII -- cell motility -- endothelial biology -- STAT3 signaling; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202002755R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: 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 CaMKIIδ promotes thrombin‐induced endothelial permeability and recent reports that CaMKII may contribute to inflammatory remodeling in the heart, we investigated CaMKIIδ‐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), CaMKIIδ 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 CaMKIIδ expression. Under these conditions, rather than promoting IL‐6‐induced permeability, we found that CaMKIIδ 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 CaMKIIδ 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. CaMKIIδ 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 CaMKIIδ, with significantly reduced vascular outgrowth and number of junctions in the developing P6 retina. For the first time, we demonstrate that transcriptional regulation of CaMKIIδ by STAT3 promotes endothelial motility, proliferation, and in vivo angiogenesis.