Figure 5. Control of TGFβ and PDGF signaling and protection of vascular wall integrity by LRP1.

Absence of LRP1 results in increased activation of TGFβ signaling. This is accompanied by disruption of elastic layers, tortuous aortas and increased fibrosis similar to what is observed in Marfan and Marfan-like syndromes in which the genes for fibrillin-1 or TGFβ receptors are defective. Loss of LRP1 expression leads to increased expression of PDGF receptors. LRP1 also controls PDGFRβ signaling and trafficking through an independent mechanism, and absence of LRP1 promotes VSMC proliferation and severe atherosclerosis. Rosiglitazone blocks TGFβ signaling upstream of PDGFR, which is inhibited by Gleevec. Both drugs are thus effective in reducing arterial wall thickening and atherosclerosis, which are induced by increased PDGFR signaling.