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.
Paye
Julie M D
JM
Angiogenesis Research Center, Section of Cardiology, Dartmouth Medical School, Hanover, New Hampshire, USA.
Phng
Li-Kun
LK
Lanahan
Anthony A
AA
Gerhard
Holger
H
Simons
Michael
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D000077214:Becaplermin; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C115271:Gipc1 protein, mouse; D009479:Neuropeptides; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin