Hypoxia differentially regulates arterial and venous smooth muscle cell proliferation via PDGFR-β and VEGFR-2 expression

Alice Chanakira, Raini Dutta, Richard Charboneau, Roderick A Barke, Steven M. Santilli, Sabita Roy

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36 Scopus citations


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 hypoxiaderived 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 the investigation of 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) and platelet- derived growth factor homodimer B (PDGF-BB) expression. VEGF-A increased (2-fold) significantly (P < 0.05) in arterialderived smooth muscle cells (ASMC) under hypoxia compared with venous-derived smooth muscle cells (VSMC), which showed no significant change. VSMC showed significant (P < 0.05) increase in VEGFR-2 expression under hypoxia compared with ASMC. Incubation with VEGFR-2-neutralizing antibody/PDGFR antagonist in VSMC before addition of H-ECM resulted in decreased proliferation. ASMC 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 intimal hyperplasia have negated the fact that combinational therapy might be required to combat induction of SMC proliferation. Clinically, therapy with PDGFR antagonists plus anti-VEGFR-2 may prove to be efficacious in managing SMC proliferation in venous-derived grafts.

Original languageEnglish (US)
Pages (from-to)H1173-H1184
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number5
StatePublished - Mar 2012


  • Graft patency
  • Platelet-derived growth factor homodimer B
  • Vascular endothelial growth factor-A


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