Synectin-dependent regulation of arterial maturation

Synectin, a ubiquitously expressed PDZ scaffold protein, has been shown to be a key regulator in the formation of arterial vasculature. Examination of the retinal vasculature in synectin(-/-) mice demonstrated poor mural cell coverage of and attachment to the forming arterial tree, a defect reminiscent of retinal abnormalities observed in platelet derived growth factor (PDGF) -B(-/-) mice. Primary cultures of synectin(-/-) smooth muscle cells had normal expression of PDGFR-beta and migrated normally in response to PDGF-BB. However, expression of PDGF-BB protein, but not mRNA, was reduced in lysates from arterial, but not venous, primary synectin(-/-) endothelial cells (EC), that was restored by inhibition of proteosomal degradation. Transduction of synectin(-/-) and (+/+) EC with a bicistronic Pdgfb/gfp construct, resulted in comparable expression of green fluorescent protein in both EC populations while PDGF-BB expression was severely reduced in synectin(-/-) EC. Finally, synectin expression in synectin(-/-) arterial EC restored PDGF-BB protein levels. These results suggest that synectin deficiency results in increased degradation of PDGF-BB protein in arterial EC and, consequently, reduced recruitment of mural cells to newly forming arteries. This observation may explain the selective reduction in arterial morphogenesis observed in synectin knockout mice.