Despite intensive research studies, theories have yet to focus on the contribution of hypoxia to patency differences observed clinically between arterial vs. venous grafts. This study investigates the differential hypoxic response of smooth muscle cells (SMC) to hypoxia derived endothelial cell (EC) growth factors. Initiation of SMC proliferation under hypoxia (<5% O2) occurred only after incubation with hypoxic endothelial cell conditioned media (H-ECM). After investigating several possible growth factors in the H-ECM that may be responsible for SMC proliferation, the greatest difference was observed in vascular endothelial growth factor (VEGF-A) & platelet derived growth factor homodimer B (PDGF-BB) expression. VEGF-A increased (2 fold) significantly (p<0.05) in arterial derived smooth muscle cells (A-SMC) under hypoxia in comparison to venous derived smooth muscle cells (V-SMC) which showed no significant change. V-SMC showed significant (p<0.05) increase in VEGFR-2 expression under hypoxia in comparison to A-SMC. Incubation with VEGFR-2 neutralizing antibody / PDGFR antagonist in V-SMC prior to addition of H-ECM resulted in decreased proliferation. A-SMC proliferation under hypoxia did not decrease during incubation with VEGFR-2 neutralizing antibody but did decrease upon PDGFR antagonist incubation. Current therapies focusing on treating IH have negated the fact that combinational therapy might be required to combat induction of smooth muscle cell proliferation. Clinically therapy with PDGFR antagonists plus anti-VEGFR-2 may prove to be efficacious in managing smooth muscle cell proliferation in venous derived grafts.
- vascular smooth muscle cells
- graft patency
- Copyright © 2011, American Journal of Physiology - Heart and Circulatory Physiology