Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development

Transforming growth factor beta (TGF-beta) transmits signals through a heterotetrameric cell-surface complex of type II (TGFBR2) and type I (activin receptor-like kinase 5, ALK5; TGFBR1) serine/threonine kinase receptors, as well as Smad2/3. We have previously shown that another type I receptor, ALK1 (ACVRL1), can also mediate TGF-beta signals via BMP-activated Smads in vascular endothelial cells (ECs). Our group and others have proposed the hypothesis that two TGF-beta signaling pathways via ALK1 and ALK5 in vascular ECs may play a balancing role for controlling the proliferation and migration of ECs during angiogenesis. To address in vivo roles of this balance in vascular development, we have created a knockin mouse line that carries a lacZ reporter in the Alk5 gene locus (Alk5(lacZ)). Throughout development, a well-defined, nonubiquitous expression pattern of Alk5 expression was observed in multiple tissues, and organs. Overall, a high level of Alk5 expression was found in perichondria, periostea, and the mesenchymal layers underlying epithelia in the kidney, lung, and gallbladder. In blood vessels, contrasting to predominant Alk1 expression in arterial endothelium, Alk5 expression was localized in the medial and adventitial layers of blood vessels, but was undetectable in the intimal layer. In addition, although Alk5-null embryos exhibit a defect in the formation of vascular smooth muscle layers, the lumens of blood vessels are generated properly, which stands in contrast to the severe dilation of the vascular lumens in Alk1-null mice. These mutually exclusive expression patterns of Alk1 and Alk5 in blood vessels, as well as the undisturbed formation of the vascular lumens in Alk5-null embryos, suggest that each type I receptor has its own unique functions in vascular development. The Alk5(lacZ) mice will be a valuable resource in identifying the in vivo cellular targets of TGF-beta family signals mediated by Alk5, both during embryonic development as well as in diverse pathological conditions.