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(Circulation. 2006;113:2445-2453.)
© 2006 American Heart Association, Inc.

Vascular Medicine

High-Resolution Quantitative Computed Tomography Demonstrating Selective Enhancement of Medium-Size Collaterals by Placental Growth Factor-1 in the Mouse Ischemic Hindlimb

Weiming Li, PhD; Weiqun Shen, PhD; Robert Gill, BS; Angela Corbly, CVT; Bonita Jones, RVT; Rama Belagaje, PhD; Yuke Zhang, MA; Shaoqing Tang, PhD; Yan Chen, MA; Yan Zhai, MA; Guoming Wang, MA; Asavari Wagle, MA; Kwan Hui, PhD; Michael Westmore, PhD; Jeffrey Hanson, BA; Yun-Fei Chen, PhD; Michael Simons, MD; JaiPal Singh, PhD

From Eli Lilly and Co, Indianapolis, Ind, and the Angiogenesis Research Center (M.S.), Dartmouth Medical School, Lebanon, NH.

Correspondence to JaiPal Singh, PhD, Eli Lilly and Co, Indianapolis, IN 46285. E-mail singh_jaipal{at}lilly.com

Received September 7, 2005; revision received March 20, 2006; accepted March 23, 2006.

Background— The process of arteriogenesis after occlusion of a major artery is poorly understood. We have used high-resolution microcomputed tomography (µ-CT) imaging to define the arteriogenic response in the mouse model of hindlimb ischemia and to examine the effect of placental growth factor-1 (PlGF-1) on this process.

Methods and Results— After common femoral artery ligation, µ-CT imaging demonstrated formation of collateral vessels originating near the ligation site in the upper limb and connecting to the ischemic calf muscle region. Three-dimensional µ-CT and quantitative image analysis revealed changes in the number of segments and the segmental volume of vessels, ranging from 8 to 160 µm in diameter. The medium-size vessels (48 to 160 µm) comprising 85% of the vascular volume were the major contributor (188%) to the change in vascular volume in response to ischemia. Intramuscular injections of Ad-PlGF-1 significantly increased Sca1⁺ cells in the circulation, -actin–stained vessels, and perfusion of the ischemic hindlimb. These effects were predominantly associated with an increase in vascular volume contributed by the medium-size (96 to 144 µm) vessels as determined by µ-CT.

Conclusions— High-resolution µ-CT delineated the formation of medium-size collaterals representing a major vascular change that contributed to the restoration of vascular volume after ischemia. This effect is selectively potentiated by PlGF-1. Such selective enhancement of arteriogenesis by therapeutically administered PlGF-1 demonstrates a desirable biological activity for promoting the growth of functionally relevant vasculature.

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