Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis.
Activin receptor-like kinase 1 (ALK-1) is an orphan type I receptor of the transforming growth factor beta (TGF-beta) 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 re-adhesion and spreading to different matrices. This led us to examine the dynamic formation of adhesion complexes. We demonstrated that while beta-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 (beta-actin, paxillin, and zyxin), and 2 encoded members of the TGF-beta 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.
Lamouille
Samy
S
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.
Mallet
Christine
C
Feige
Jean-Jacques
JJ
Bailly
Sabine
S
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D030201:Activin Receptors, Type I / Q000235:genetics / Q000502:physiology*; D030301:Activin Receptors, Type II; D052006:Bone Morphogenetic Protein Receptors, Type II; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D022001:Focal Adhesions; D016193:G1 Phase; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016259:Genes, myc; D006023:Glycoproteins; D055436:Growth Differentiation Factor 15; D006801:Humans; D008168:Lung / Q000098:blood supply; D008667:Metalloproteins / Q000096:biosynthesis / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D051419:Paxillin; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012867:Skin / Q000098:blood supply; D014471:Umbilical Veins / Q000166:cytology; D060589:Zyxin
D000199:Actins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; C526140:GDF15 protein, human; D006023:Glycoproteins; D055436:Growth Differentiation Factor 15; D008667:Metalloproteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; C092842:ZYX protein, human; D060589:Zyxin; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II