EPHB4 Protein Expression in Vascular Smooth Muscle Cells Regulates Their Contractility, and EPHB4 Deletion Leads to Hypotension in Mice

• Published in: The Journal of biological chemistry Vol. 290; no. 22; pp. 14235 - 14244
• Main Authors: Wang, Yujia, Thorin, Eric, Luo, Hongyu, Tremblay, Johanne, Lavoie, Julie L., Wu, Zenghui, Peng, Junzheng, Qi, Shijie, Wu, Jiangping
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29-05-2015; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Arteries - metabolism; Blood Pressure; Calcium - metabolism; Cell Biology; EPHB4 kinases; Female; Gene Deletion; gene knockout; Genotype; GRIP1; hormone; hypertension; hypotension; Hypotension - metabolism; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction; Muscle, Smooth, Vascular - metabolism; Phosphorylation; Receptor, EphB4 - physiology; RNA, Small Interfering - metabolism; Sex Factors; sex hormones; Signal Transduction; vascular smooth muscle cells; hypotension; gene knockout; GRIP1; cell biology; sex hormones; EPHB4 kinases; hypertension; vascular smooth muscle cells; hormone
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.621615

EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with 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 Ca2+/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, 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 blood pressure.
Background: The role of EPHB4 blood pressure regulation was not previously known.
Results: Male but not female smooth muscle cell-specific Ephb4 gene knock-out mice were hypotensive; bi-directional signaling between EFNBs and EPHB4 modulated small artery contractility.
Conclusion: EPHB4 in vascular smooth muscle cells regulates blood pressure.
Significance: A new mechanism of blood pressure regulation has been discovered.