HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/H1891    most recent 00537.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Zbinden, S. Articles by Epstein, S. E. Search for Related Content PubMed PubMed Citation Articles by Zbinden, S. Articles by Epstein, S. E.

Interanimal variability in preexisting collaterals is a major factor determining outcome in experimental angiogenesis trials

¹Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, District of Columbia; and ²Department of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota

Submitted 25 May 2006 ; accepted in final form 5 December 2006

Despite numerous animal trials reporting that cell therapy promotes collateral flow, clinical trials have not convincingly shown benefit. Patient-related risk factors are often used to explain these discrepancies. However, during the course of our own angiogenesis studies using mice, we noted large anatomical variability in collateral vessels. The purpose of the present investigation was to define how important this factor might be in determining intervention outcomes. Hindlimb ischemia was induced in BALB/c mice by ligating the superficial femoral artery. After 24 h, animals were treated by injecting the adductor muscle with either control media or cultured mesenchymal stem cells (MSCs). Blood flow recovery was measured using laser-Doppler [laser-Doppler perfusion imaging (LDPI) ratio]. In a second experiment, mice were stratified 24 h after arterial ligation before treatment by using a simple clinical score of the ligated leg: 1, able to flex, mild discoloration; 2, no flexion, mild discoloration; 3, severe discoloration; and 4, any necrosis. Without stratification, blood flow recovery significantly increased in the MSC-treated group (P < 0.05, n = 6 MSC group, n = 7 media group). In the experiment employing stratification, all differences between the groups disappeared (n = 11 MSC group, n = 10 media group; P = 0.3). Furthermore, we found a striking inverse correlation between clinical score on day 1 and the LDPI ratio on day 28 (P < 0.0001; n = 79). Anatomical confirmation of the disparity in preexisting collaterals was found in two different mouse strains using microscopic computed tomography. In conclusion, there is substantial interanimal variability in preexisting collateral flow, and this variability can importantly influence outcome. To overcome this, either animals must be stratified before treatment, the number of animals must be increased substantially, or, preferably, both.

stem cell; study design

This article has been cited by other articles:

				W. M. Chilian and Y. F. Pung Vascular Endothelial Growth Factor and the Collateral Circulation: The Story Continues Circ. Res., October 24, 2008; 103(9): 905 - 906. [Full Text] [PDF]

				K. M. Sheridan, M. J. Ferguson, M. R. Distasi, F. A. Witzmann, M. C. Dalsing, S. J. Miller, and J. L. Unthank Impact of genetic background and aging on mesenteric collateral growth capacity in Fischer 344, Brown Norway, and Fischer 344 x Brown Norway hybrid rats Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3498 - H3505. [Abstract] [Full Text] [PDF]