Both type I TGFβ Receptors ALK‐1 and ALK‐5 Promote Inhibition of Endothelial Cell Proliferation Mediated by TGFβ1

Abstract

Control of angiogenesis is critical in diseases such as cancer, heart disease, or wound repair. Growth factors such as transforming growth factor beta (TGFβ) and fibroblast growth factor 2 (FGF‐2) contribute to angiogenesis. We have examined the effects of TGFβ and the TGFβ family signaling type I receptors Activin‐Like Kinase 1 Receptor (ALK‐1) and ALK‐5 and their effects on endothelial cell growth. We report that TGFβ inhibits both DNA synthesis and also Cyclin A promoter‐luciferase expression stimulated by FGF‐2 or serum. We also show data that TGFβ also decreases cyclin A and cyclin D1 protein expression in endothelial cells (EC). In previous work it has been shown that FGF‐2 is tranlocated to the nucleus as a part of its positive stimulatory growth of EC and other cell types. We also show that TGFβ blocks nuclear translocation of FGF‐2 but not FGF‐2 stimulation of Mitogen Activated Protein Kinase (MAP) Kinase activity. TGFβ can bind and activate both ALK‐1 and ALK‐5 in endothelial cells. Transfection of either activated ALK‐1 or activated ALK‐5 QD (kinase activated) plasmids into endothelial cells increased inhibition of DNA synthesis mediated by TGFβ. This data indicates that the growth inhibitory effects of TGFβ are mediated through both ALK‐1 and ALK‐5 type I receptors in endothelial cells. We have also shown that ALK‐1 is also involved in endothelial tube formation or angiogenesis. Other ligands such as Bone Morphogenetic Protein 9 (BMP‐9) and Activin A may also be involved in endothelial cell function. Thus we are also looking at expression of various ALK‐1 ligands and co‐receptors in endothelial cells under various conditions and we are generating mutants of ALK‐1, ALK‐5, and endoglin to further test their roles in angiogenesis.Support or Funding InformationResearch support was from AHA and Dept Veteran's Affairs grants (JH) and funds from Saint Leo University (ID).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.