Peroxisome proliferator-activated receptor-delta agonist enhances vasculogenesis by regulating endothelial progenitor cells through genomic and nongenomic activations of the phosphatidylinositol 3-kinase/Akt pathway.
BACKGROUND
Despite the therapeutic potential of endothelial progenitor cells (EPCs) in ischemic vascular diseases, their insufficient numbers limit clinical applications. Peroxisome proliferator-activated receptor (PPAR)-delta belongs to the nuclear hormone receptor superfamily, and its functions in various tissues and cells are almost unexplored, especially with respect to vascular biology.


RESULTS
PPAR-delta activation in EPCs phosphorylated Akt, and this phosphorylation was mediated not only by genomic but also by nongenomic pathways through interaction with the regulatory subunit of phosphatidylinositol 3-kinase. PPAR-delta activation with agonist (GW501516 or L-165041) increased the proliferation of human EPCs and protected them from hypoxia-induced apoptosis. In addition, PPAR-delta activation enhanced EPC functions, such as transendothelial migration, and tube formation. These actions by PPAR-delta activation in EPCs were dependent on the phosphatidylinositol 3-kinase/Akt pathway. In ischemic hindlimb of mice models, transplantation of PPAR-delta agonist-treated human or mouse EPCs enhanced blood flow recovery to ischemic limbs compared with vehicle-treated EPCs. In EPCs from PPAR-delta-knockout mice, however, treatment with PPAR-delta agonist did not enhance in vivo vasculogenic potential. Systemic administration of PPAR-delta agonist increased hematopoietic stem cells in bone marrow and EPCs in peripheral blood, leading to improved vasculogenesis with incorporation of bone marrow-derived cells to new vessels in a corneal neovascularization model and limb salvage with better blood flow in an ischemic hindlimb model.


CONCLUSIONS
The results of our study suggest that PPAR-delta agonist has therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases.
Han
Jung-Kyu
JK
Cardiovascular Center, Seoul National University Hospital, 28 Yongon-dong Chongno-gu, Seoul 110-744, Korea.
Lee
Hyun-Sook
HS
Yang
Han-Mo
HM
Hur
Jin
J
Jun
Soo-In
SI
Kim
Ju-Young
JY
Cho
Chung-Hyun
CH
Koh
Gou-Young
GY
Peters
Jeffrey M
JM
Park
Kyung-Woo
KW
Cho
Hyun-Jai
HJ
Lee
Hae-Young
HY
Kang
Hyun-Jae
HJ
Oh
Byung-Hee
BH
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001853:Bone Marrow / Q000378:metabolism; D002478:Cells, Cultured; D016510:Corneal Neovascularization / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006614:Hindlimb / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D033581:Stem Cell Transplantation; D013844:Thiazoles / Q000494:pharmacology*; D014652:Vascular Diseases / Q000378:metabolism* / Q000473:pathology / Q000628:therapy
C425931:GW 501516; D047494:PPAR delta; D013844:Thiazoles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt