title: Hypoxia differentially regulates arterial and venous smooth muscle cell proliferation via PDGFR-β and VEGFR-2 expression.
abstract: 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% O(2)) 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 arterial-derived 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.
authors.affiliation: Dept. of Pharmacology, University of Minnesota, 11 6-125 Jackson Hall, 312 Church Street South East, Minneapolis, MN 55455, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Chanakira
authors.forename: Raini
authors.initials: R
authors.lastname: Dutta
authors.forename: Richard
authors.initials: R
authors.lastname: Charboneau
authors.forename: Roderick
authors.initials: R
authors.lastname: Barke
authors.forename: Steven M
authors.initials: SM
authors.lastname: Santilli
authors.forename: Sabita
authors.initials: S
authors.lastname: Roy
mesh_terms: D001158:Arteries / Q000378:metabolism; D000077214:Becaplermin; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014680:Veins / Q000378:metabolism
chemical_list: D020574:Proto-Oncogene Proteins c-sis; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2