EPHB4 expression in vascular smooth muscle cells regulates their contractility and EPHB4 deletion leads to hypotension in mice [Gene Regulation]

April 22nd, 2015 by Wang, Y., Thorin, E., Luo, H., Tremblay, J., Lavoie, J. L., Wu, Z., Peng, J., Qi, S., Wu, J.

EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work present evidencethat EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure (BP) regulation. We generated gene knockout (KO) mice with smooth muscle cell-specific deletion of EPHB4. Male not female KO mice were hypotensive. VSMCs from male KO mice showed reduced contractility compared to their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from CamKII to MLCK to MLC, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and BP.
  • Posted in Journal of Biological Chemistry, Publications
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