Abstract 1643: The BMP Receptor II is Localized in the Endothelial Cell Junction and plays a Paradoxical Role as Both a Pro- and an Anti-inflammatory Regulator
Atherosclerosis is known as an inflammatory disease, occurring preferentially in branched or curved arteries associated with unstable flow including oscillatory shear stress (OS). We have shown that bone morphogenic protein 4 (BMP4) produced in endothelial cells by OS stimulates inflammatory responses as determined by ICAM-1 induction and monocyte adhesion. To determine the mechanism by which BMP4 induces the inflammatory response, we examined which BMP receptors are expressed in mouse aortic endothelial cells (MAEC) and mouse aortas. RT-PCR, Western blot, and immunohistochemical staining analyses revealed that BMPRI (ALK2) and BMPRII are the major BMP receptors expressed in MAEC and mouse thoracic aortic endothelium. Interestingly, BMPRII is found mainly in the endothelial cell-cell junction, colocalizing with VE-cadherin, in confluent MAEC but not in subconfluent or wounded cells. Knocking down BMPRII protein levels by siRNA prevented BMP4-induced monocyte adhesion to MAEC and human umbilical vein EC (HUVEC), suggesting the essential role of BMPRII in BMP4-induced inflammation. Unexpectedly, however, the BMPRII-knockdown also significantly increased monocyte adhesion and ICAM-1 expression in the basal condition in comparison to the non-silencing control. Monocyte adhesion induced by BMPRII knockdown was abolished by the YN1 ICAM-1 blocking antibody. These results suggest that the BMPRII plays a paradoxical role: one that mediates inflammation upon BMP4 binding and another that constitutively prevents inflammation in the basal condition as revealed by the siRNA study. Since the loss-of-function mutations of BMPRII are known to induce primary pulmonary hypertension, a disease characterized by uncontrolled endothelial proliferation and inflammation, it is important to study whether our findings are involved in this disease as well as atherosclerosis.