Pleiotrophin induces nitric oxide dependent migration of endothelial progenitor cells.
Pleiotrophin (PTN) is produced under ischemic conditions and has been shown to induce angiogenesis in vivo. We studied whether or not PTN exerts chemotaxis of pro-angiogenic early endothelial progenitor cells (EPCs), a population of circulating cells that have been reported to participate in and stimulate angiogenesis. Chemotaxis of EPCs, isolated from blood of healthy humans (n = 5), was measured in transwell assays. PTN at 10-500 ng/ml elicited dose-dependent chemotaxis of both EPCs and human umbilical vein endothelial cells (HUVECs), but not of human coronary artery smooth muscle cells (CASMCs) and T98G glioblastoma cells that lack PTN receptors. The degree of chemotaxis was comparable to that induced by the angiogenic factors VEGF and SDF-1alpha. Chemotaxis to PTN was blocked by the NOS inhibitors L-NNA and L-NMMA, the NO scavenger PTIO, the phosphoinositide-3 kinase inhibitor wortmannin, and the guanylyl cyclase inhibitor ODQ, suggesting dependence of EPC chemotaxis on these pathways. PTN induced NOS-dependent production of NO to a similar degree as did VEGF, as indicated by the NO indicator DAF-2. PTN increased proliferation in EPCs and HUVECs to a similar extent as VEGF, but did not induce proliferation of CASMCs. While L-NNA abolished PTN-induced migration in EPCs and HUVECs, it did not inhibit PTN- and VEGF-enhanced proliferation and also caused proliferation by itself. These data suggest that PTN may mediate its pro-angiogenic effects by increasing the local number of not only endothelial cells but also early EPCs at angiogenic sites.
Heiss
Christian
C
Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, California 94143-0124, USA.
Wong
Maelene L
ML
Block
Vanessa I
VI
Lao
David
D
Real
Wendy May
WM
Yeghiazarians
Yerem
Y
Lee
Randall J
RJ
Springer
Matthew L
ML
D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002352:Carrier Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects*; D016207:Cytokines / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D043925:Angiogenesis Inducing Agents; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; C066845:pleiotrophin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase