Thrombospondin-1-induced smooth muscle cell chemotaxis and proliferation are dependent on transforming growth factor-[beta]2 and hyaluronic acid synthase

Angioplasty causes local vascular injury, leading to the release of thrombospondin-1 (TSP-1), which stimulates vascular smooth muscle cell (VSMC) migration and proliferation, important steps in the development of intimal hyperplasia. Transforming growth factor beta 2 (TGF-[beta]2) and hyaluronic acid synthase (HAS) are two pro-stenotic genes upregulated in VSMCs by TSP-1. We hypothesized that inhibition of TGF-[beta]2 or HAS would inhibit TSP-1-induced VSMC migration, proliferation, and TSP-1 signaling. Our data demonstrate that Inhibition of either TGF-[beta]2 or HAS inhibited TSP-1-induced VSMC migration and proliferation. Activation of ERK 1 was decreased by TGF-[beta]2 inhibition and unaffected by HAS inhibition. TGF-[beta]2 and HAS are not implicated in TSP-1-induced thbs1 expression, while they are each implicated in TSP-1-induced expression of their own gene. In summary, TSP-1-induced VSMC migration and proliferation rely on intact TGF-[beta]2 signaling and HAS function. TSP-1 activation of ERK 1 is dependent on TGF-[beta]2. These data further expand our understanding of the complexity of TSP-1 cellular signaling and the involvement of TGF-[beta]2 and HAS.[PUBLICATION ABSTRACT]