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PMID:12453878

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Citation

Lamouille, S, Mallet, C, Feige, JJ and Bailly, S (2002) Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis. Blood 100:4495-501

Abstract

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.

Links

PubMed Online version:10.1182/blood.V100.13.4495

Keywords

Actins/biosynthesis; Actins/genetics; Activin Receptors, Type I/genetics; Activin Receptors, Type I/physiology; Activin Receptors, Type II; Bone Morphogenetic Protein Receptors, Type II; Cell Division; Cell Movement; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; Cyclins/biosynthesis; Cyclins/genetics; Cytokines/biosynthesis; Cytokines/genetics; Cytoskeletal Proteins/biosynthesis; Cytoskeletal Proteins/genetics; DNA, Complementary/genetics; Endothelium, Vascular/cytology; Endothelium, Vascular/metabolism; Focal Adhesions; G1 Phase; Gene Expression Profiling; Gene Expression Regulation; Genes, myc; Glycoproteins; Growth Differentiation Factor 15; Humans; Lung/blood supply; Metalloproteins/biosynthesis; Metalloproteins/genetics; Neovascularization, Physiologic/genetics; Neovascularization, Physiologic/physiology; Oligonucleotide Array Sequence Analysis; Organ Specificity; Paxillin; Phosphoproteins/biosynthesis; Phosphoproteins/genetics; Protein-Serine-Threonine Kinases/biosynthesis; Protein-Serine-Threonine Kinases/genetics; Proto-Oncogene Proteins c-myc/biosynthesis; Recombinant Fusion Proteins/physiology; Skin/blood supply; Umbilical Veins/cytology; Zyxin

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ACVL1

involved_in

GO:0051895: negative regulation of focal adhesion assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ACVL1

involved_in

GO:0035313: wound healing, spreading of epidermal cells

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ACVL1

involved_in

GO:0030336: negative regulation of cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ACVL1

involved_in

GO:0008285: negative regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ACVL1

involved_in

GO:0007162: negative regulation of cell adhesion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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