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Blood, 15 December 2002, Vol. 100, No. 13, pp. 4495-4501
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Activin receptor-like kinase 1 is implicated in the
maturation phase of angiogenesis
Samy Lamouille,
Christine Mallet,
Jean-Jacques Feige, and
Sabine Bailly
From Institut National de la Santé et de la
Recherche Médicale (INSERM) EMI 0105, Department of Responses and
Cellular Dynamics, Commissariat à l'Energie (CEA)-Grenoble,
France.
Activin receptor-like kinase 1 (ALK-1) is an orphan type I
receptor of the transforming growth factor beta (TGF- ) 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 (HMVEC-d'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 -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 (-actin, paxillin, and zyxin), and 2 encoded members of the
TGF- family (BMPRII and GDF-15). Taken together, our results suggest
that ALK-1 is implicated in the maturation phase of angiogenesis.
Disruption of this latter phase of angiogenesis may be an important
step in the development of hereditary hemorrhagic telangiectasia.
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