Modulating Notch signaling to enhance neovascularization and reperfusion in diabetic mice

被引:34
作者
Cao, Lan [1 ,2 ]
Arany, Praveen R. [1 ,3 ,4 ]
Kim, Jaeyun [1 ,2 ]
Rivera-Feliciano, Jose [1 ]
Wang, Yuan-Shuo [1 ]
He, Zhiheng [5 ]
Rask-Madsen, Christian [5 ]
King, George L. [5 ]
Mooney, David J. [1 ,2 ]
机构
[1] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA
[2] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA
[3] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA
[4] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA
[5] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Vasc Cell Biol, Boston, MA 02115 USA
关键词
VEGF; Angiogenesis; Notch Signaling; Diabetes; Ischemia; Alginate; PROGENITOR-CELL DYSFUNCTION; GROWTH-FACTOR EXPRESSION; INHIBITS TUMOR-GROWTH; ENDOTHELIAL-CELLS; VASCULAR DEVELOPMENT; VEGF RESPONSIVENESS; INSULIN-RESISTANCE; ANGIOGENESIS; MELLITUS; MYOCARDIUM;
D O I
10.1016/j.biomaterials.2010.08.002
中图分类号
R318 [生物医学工程];
学科分类号
100103 [病原生物学];
摘要
Diabetes can diminish the responsiveness to angiogenic factors (e.g., VEGF) important for wound healing and the treatment of ischemic diseases, and this study investigated the hypothesis that this effect can be reversed by altering Notch signaling. Aortic endothelial cells (ECs) isolated from diabetic mice demonstrated reduced sprouting capability in vitro, but adding a Notch inhibitor (DAPT) led to cell-density and VEGF-dose dependent enhancement of proliferation, migration and sprouting, in both 2-D and 3-D cultures, as compared to VEGF alone. The in vivo effects of VEGF and DAPT were tested in the ischemic hind limbs of diabetic mice. Combining VEGF and DAFT delivery resulted in increased blood vessel density (similar to 150%) and improved tissue perfusion (similar to 160%), as compared to VEGF alone. To examine if DAFT would interfere with vessel maturation, DAPT was also delivered with a combination of VEGF and platelet derived growth factor (PDGF). DAPT and PDGF did not interfere with the effects of the other, and highly functional and mature networks of vessels could be formed with appropriate delivery. In summary, modulating Notch signaling enhances neovascularization and perfusion recovery in diabetic mice suffering from ischemia, suggesting this approach could have utility for human diabetics. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码:9048 / 9056
页数:9
相关论文
共 48 条
[1]
Notch signaling: Cell fate control and signal integration in development [J].
Artavanis-Tsakonas, S ;
Rand, MD ;
Lake, RJ .
SCIENCE, 1999, 284 (5415) :770-776
[2]
Notch signalling: a simple pathway becomes complex [J].
Bray, Sarah J. .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2006, 7 (09) :678-689
[3]
Promoting angiogenesis via manipulation of VEGF responsiveness with notch signaling [J].
Cao, Lan ;
Arany, Praveen R. ;
Wang, Yuan-Shuo ;
Mooney, David J. .
BIOMATERIALS, 2009, 30 (25) :4085-4093
[4]
Involvement of Notch Signaling in Wound Healing [J].
Chigurupati, Srinivasulu ;
Arumugam, Thiruma V. ;
Son, Tae Gen ;
Lathia, Justin D. ;
Jameel, Shafaq ;
Mughal, Mohamed R. ;
Tang, Sung-Chun ;
Jo, Dong-Gyu ;
Camandola, Simonetta ;
Giunta, Marialuisa ;
Rakova, Irina ;
McDonnell, Nazli ;
Miele, Lucio ;
Mattson, Mark P. ;
Poosala, Suresh .
PLOS ONE, 2007, 2 (11)
[5]
Couffinhal T, 1998, AM J PATHOL, V152, P1667
[6]
Endothelial cell dysfunction and the vascular complications associated with type 2 diabetes: assessing the health of the endothelium [J].
Ding, Hong ;
Triggle, Chris .
VASCULAR HEALTH AND RISK MANAGEMENT, 2005, 1 (01) :55-71
[7]
Hyperbaric oxygen and bone marrow-derived endothelial progenitor cells in diabetic wound healing [J].
Gallagher, Katherine A. ;
Goldstein, Lee J. ;
Thom, Stephen R. ;
Velazquez, Omaida C. .
VASCULAR, 2006, 14 (06) :328-337
[8]
VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia [J].
Gerhardt, H ;
Golding, M ;
Fruttiger, M ;
Ruhrberg, C ;
Lundkvist, A ;
Abramsson, A ;
Jeltsch, M ;
Mitchell, C ;
Alitalo, K ;
Shima, D ;
Betsholtz, C .
JOURNAL OF CELL BIOLOGY, 2003, 161 (06) :1163-1177
[9]
Notch signaling in vascular development and physiology [J].
Gridley, Thomas .
DEVELOPMENT, 2007, 134 (15) :2709-2718
[10]
Diabetes and cardiovascular disease - A statement for healthcare professionals from the American Heart Association [J].
Grundy, SM ;
Benjamin, IJ ;
Burke, GL ;
Chait, A ;
Eckel, RH ;
Howard, BV ;
Mitch, W ;
Smith, SC ;
Sowers, JR .
CIRCULATION, 1999, 100 (10) :1134-1146