Published Online
on May 15, 2006

A more recent version of this article appeared on May 23, 2006

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Submitted on September 7, 2005
Revised on March 20, 2006
Accepted on March 23, 2006

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, and JaiPal Singh PhD^*

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

^* To whom correspondence should be addressed. E-mail: singh_jaipal{at}lilly.com.

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.

Key words: angiogenesis • gene therapy • growth substances • ischemia

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