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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:813.)
© 2007 American Heart Association, Inc.

Vascular Biology

Reconstituted High-Density Lipoprotein Stimulates Differentiation of Endothelial Progenitor Cells and Enhances Ischemia-Induced Angiogenesis

Makoto Sumi; Masataka Sata; Shin-ichiro Miura; Kerry-Anne Rye; Naoki Toya; Yuji Kanaoka; Katsuhiko Yanaga; Takao Ohki; Keijiro Saku; Ryozo Nagai

From the Department of Cardiovascular Medicine (M. Sumi, M. Sata, R.N.), University of Tokyo Graduate School of Medicine, Japan; Department of Surgery (M. Sumi, N.T., Y.K., K.Y., T.O.), Jikei University School of Medicine, Tokyo, Japan; Department of Advanced Clinical Science and Therapeutics (M. Sata), University of Tokyo Graduate School of Medicine, Japan; Department of Cardiology (S.M., K.S.), Fukuoka University School of Medicine, Japan; and Heart Research Institute (K.-A.R.), Sydney, Australia.

Correspondence to Masataka Sata, MD, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail msata-circ{at}umin.net

Background— Plasma high-density lipoprotein (HDL) levels have an inverse correlation with incidence of ischemic heart disease as well as other atherosclerosis-related ischemic conditions. However, the molecular mechanism by which HDL prevents ischemic disease is not fully understood. Here, we investigated the effect of HDL on differentiation of endothelial progenitor cells and angiogenesis in murine ischemic hindlimb model.

Methods and Results— Intravenous injection of reconstituted HDL (rHDL) significantly augmented blood flow recovery and increased capillary density in the ischemic leg. rHDL increased the number of bone marrow–derived cells incorporated into the newly formed capillaries in ischemic muscle. rHDL induced phosphorylation of Akt in human peripheral mononuclear cells. rHDL (50 to 100 µg apolipoprotein A-I/mL) promoted differentiation of peripheral mononuclear cells to endothelial progenitor cells in a dose-dependent manner. The effect of rHDL on endothelial progenitor cells differentiation was abrogated by coadministration of LY294002, an inhibitor of phosphatidylinositol 3-kinase. rHDL failed to promote angiogenesis in endothelial NO–deficient mice.

Conclusions— rHDL directly stimulates endothelial progenitor cell differentiation via phosphatidylinositol 3-kinase/Akt pathway and enhances ischemia-induced angiogenesis. rHDL may be useful in the treatment of patients with ischemic cardiovascular diseases.

Reconstituted HDL (rHDL) augmented angiogenesis in ischemic hindlimb with enhanced incorporation of bone marrow–derived cells in new vessels. rHDL promoted differentiation of endothelial progenitor cells via PI3K/Akt pathway. The beneficial effect of rHDL was abrogated in eNOS-deficient mice. rHDL might be useful in therapeutic angiogenesis.

Key Words: high-density lipoproteins • endothelial progenitor cells • angiogenesis • mouse • collateral

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