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

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4495-4501 ◽  
Author(s):  
Samy Lamouille ◽  
Christine Mallet ◽  
Jean-Jacques Feige ◽  
Sabine Bailly

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 (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 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 angiogenesis. Disruption of this latter phase of angiogenesis may be an important step in the development of hereditary hemorrhagic telangiectasia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3105-3105
Author(s):  
Shalom Avraham ◽  
Shuxian Jiang ◽  
Tae-Hee Lee ◽  
O. Prakash ◽  
Hava Karsenty Avraham

Abstract The blood-brain barrier (BBB) is a network formed mainly by brain microvascular endothelial cells. The integrity of the BBB is critical for brain function. Breakdown of the BBB is commonly seen in AIDS patients with HIV-1-associated dementia (HAD), despite the lack of productive HIV-infection of the brain endothelium. The processes by which HIV causes these pathological conditions are not well understood. Here, we characterized the molecular mechanisms by which Tat mediates its pathogenic effects in-vitro on primary human brain microvascular endothelial cells (HBMECs). Tat treatment of HBMECs stimulated cytoskeletal organization and increased focal adhesion sites as compared to control cells or cells treated with heat-inactivated Tat. Pretreatment with Tat antibodies or with the specific inhibitor SU-1498, which interferes with VEGFR-2 (Flk-1/KDR) receptor phosphorylation, blocked the ability of Tat to stimulate focal adhesion assembly and the migration of HBMECs. Focal adhesion kinase (FAK) was tyrosine-phosphorylated by Tat and found to be an important component of focal adhesion sites. Inhibition of FAK by the dominant-interfering mutant form FRNK (FAK-related non-kinase) significantly blocked HBMEC migration and disrupted focal adhesions upon Tat activation. Furthermore, HIV-Tat induced permeability changes in HBMECs in a time dependent manner. Tat also impaired BBB permeability as observed in HIV-1 Tat transgenic mice. These studies define a mechanism for HIV-1 Tat in focal adhesion complex assembly in HBMECs, via activation of FAK, leading to cytoskeletal reorganization and permeability changes.


2012 ◽  
Vol 11 (S1) ◽  
Author(s):  
Nicoletta Basilico ◽  
Daniela Girelli ◽  
Sarah D’Alessandro ◽  
Yolanda Corbett ◽  
Mauro Prato ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document