Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis

Abstract

Activin receptor-like kinase 1 (ALK-1) is an orphan type I receptor of the transforming growth factor beta (TGF-β) receptor family. In vivo studies have demonstrated that this endothelial-specific receptor is implicated in angiogenesis. In this study, we addressed the cellular function of ALK-1 in cultured human microvascular endothelial cells from the dermis (HMVECd's) using adenoviral expression of a constitutively active form of ALK-1 (ALK-1QD). We observed that ALK-1QD expression inhibits cell proliferation through an arrest in the G1 phase in the cell cycle. ALK-1QD expression also inhibited migration. This inhibition was also observed in other endothelial cells (human microvascular endothelial cells [HMEC-1's], HMVECs from the lung, and human umbilical vein endothelial cells [HUVECs]). Finally, ALK-1QD expression decreased readhesion and spreading to different matrices. This led us to examine the dynamic formation of adhesion complexes. We demonstrated that while β-gal-infected cells reorganized actin stress fibers and focal adhesion complexes at the edge of a wound, ALK-1QD-infected cells did not. To identify downstream genes implicated in ALK-1 cellular responses, we next performed a cDNA array analysis of the expressed genes. There were 13 genes found to be significantly induced or suppressed by ALK-1QD. Among them, 2 genes encoded cell cycle-related proteins (c-myc and p21/waf1), 3 encoded components of the cytoskeleton-focal adhesion complex (β-actin, paxillin, and zyxin), and 2 encoded members of the TGF-β family (BMPRII and GDF-15). Taken together, our results suggest that ALK-1 is implicated in the maturation phase of angiogenesJs anglogenesis. Disruption of this latter phase of angiogenesis may be an important step In the development of hereditary hemorrhagic telangiectasia. © 2002 by The American Society of Hematology.