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NGF Promotes Hemodynamic Recovery in a Rabbit Hindlimb Ischemic Model Through trkA- and VEGFR2-dependent Pathways

Karatzas, Andreas MD*; Katsanos, Konstantinos MD, PhD*; Lilis, Ioannis MSc; Papadaki, Helen MD, PhD; Kitrou, Panagiotis MD*; Lecht, Shimon PhD‡,§; Marcinkiewicz, Cezary PhD; Siablis, Dimitris MD, PhD*; Lelkes, Peter I. PhD; Lazarovici, Philip PhD§; Tsopanoglou, Nikos E. PhD

Journal of Cardiovascular Pharmacology: September 2013 - Volume 62 - Issue 3 - p 270–277
doi: 10.1097/FJC.0b013e3182982de7
Original Article

Abstract: Nerve growth factor (NGF) has been reported to play an important role in physiological and pathological angiogenesis. Based on these observations, we hypothesized that NGF may induce the formation of functional blood vessels in a hindlimb ischemic rabbit model. Hindlimb ischemia was induced in 34 rabbits bilaterally by endovascular embolization of femoral arteries. On the 7th, 14th, and 20th postembolization days, NGF was injected intramuscularly, in 1 ischemic limb, and vehicle was injected in the contralateral control limb. On the 40th day, newly developed collateral vessels (diameter >500 μm) were quantified by transauricular intraarterial subtraction angiography. Perfusion analysis of an in vivo dynamic computed tomography study was performed to the limbs to investigate the hemodynamic recovery of the distal ischemic tissues. Functional estimation of limb perfusion showed a statistically significant increase of blood flow and blood volume for NGF. However, the increase of the collateral vessels was not detectable angiographically, providing evidence for the existence of a NGF-stimulated capillary angiogenic network but not increase of arteriogenesis. The combination of NGF with either tropomyosin-related kinase type A or vascular endothelial growth factor receptor 2 antagonists abolished the NGF-induced hemodynamic recovery. These findings provide new insights into understanding the involvement of NGF in vascular formation and its applications in therapeutic angiogenesis.

*Departments of Radiology and

Anatomy, Histology, and Embryology, Medical School, University of Patras, Patras, Greece;

Department of Bioengineering, College of Engineering, Temple University, Philadelphia, PA;

§School of Pharmacy, Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel;

Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA; and

Department of Pharmacology, Medical School, University of Patras, Patras, Greece.

Reprints: Nikos E. Tsopanoglou, PhD, Department of Pharmacology, Medical School, University of Patras, 26504 Patras, Greece (e-mail:

Supported by a grant from the Greek Central Council of Health. P. Lazarovici holds The Jacob Gitlin Chair in Physiology and is affiliated and partially supported by the David R. Bloom Center for Pharmacy and the Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel.

The authors report no conflicts of interest.

Received February 06, 2013

Accepted April 22, 2013

© 2013 by Lippincott Williams & Wilkins.