The ALK-1/Smad1 pathway in cardiovascular physiopathology. A new target for therapy?

Abstract

Activin receptor-like kinase-1 or ALK-1 is a type I cell surface receptor for the transforming growth factor-β (TGF-β) family of proteins. The role of ALK-1 in endothelial cells biology and in angiogenesis has been thoroughly studied by many authors. However, it has been recently suggested a possible role of ALK-1 in cardiovascular homeostasis. ALK-1 is not only expressed in endothelial cells but also in smooth muscle cells, myofibroblast, hepatic stellate cells, chondrocytes, monocytes, myoblasts, macrophages or fibroblasts, but its role in these cells have not been deeply analyzed. Due to the function of ALK-1 in these cells, this receptor plays a role in several cardiovascular diseases. Animals with ALK-1 haploinsufficiency and patients with mutations in Acvrl1 (the gene that codifies for ALK-1) develop type-2 Hereditary Hemorrhagic Telangiectasia. Moreover, ALK-1 heterozygous mice develop pulmonary hypertension. Higher levels of ALK-1 have been observed in atherosclerotic plaques, suggesting a possible protector role of this receptor. ALK-1 deficiency is also related to the development of arteriovenous malformations (AVMs). Besides, due to the ability of ALK-1 to regulate cell proliferation and migration, and to modulate extracellular matrix (ECM) protein expression in several cell types, ALK-1 has been now demonstrated to play an important role in cardiovascular remodeling. In this review, we would like to offer a complete vision of the role of ALK-1 in many process related to cardiovascular homeostasis, and the involvement of this protein in the development of cardiovascular diseases, suggesting the possibility of using the ALK-1/smad-1 pathway as a powerful therapeutic target.

Keywords: Angiogenesis; Arteriovenous malformation; HHT; Pulmonary hypertension; Smads; TGF-β.