Skin-derived microorgan autotransplantation as a novel approach for therapeutic angiogenesis.
Despite promising preclinical results, transient single-factor-based therapeutic angiogenesis has shown no definitive benefits in clinical trials. The use of skin-derived microorgans (SMOs), capable of sustained expression of angiogenic factors and sustained viability with their cellular and extracellular elements, constitutes an attractive alternative. We sought to evaluate the efficacy of SMO implantation in a porcine model of chronic myocardial ischemia. Eighteen pigs underwent placement of an ameroid constrictor on the proximal circumflex artery. Three weeks later, split-thickness skin biopsies were harvested and pigs were randomized to lateral wall implantation of either 8 or 16 SMOs or blank injections. The procedure was safe and resulted in no adverse events. Three weeks after treatment, SMO implantation resulted in significant improvement of lateral wall perfusion during pacing, assessed by isotope-labeled microspheres [post- vs. pretreatment ratios of lateral/anterior wall blood flow were 1.31 +/- 0.09 (SMOs) and 1.04 +/- 0.06 (controls); P = 0.03]. No significant difference in angiographic scores was observed. Microvascular relaxation in response to VEGF was impaired in the ischemic territory of the control group but returned to normal after SMO implantation, indicating restoration of endothelial function. Molecular studies showed significant increases in VEGF and CD31 expression in the ischemic area of treated animals. Morphometric analysis showed increased neovascularization with SMO treatment. Autotransplantation of SMOs constitutes a novel approach for safe and effective therapeutic angiogenesis with improvement in perfusion, normalization of microvascular reactivity, and increased expression of VEGF and CD31.
Voisine
Pierre
P
Angiogenesis Research Center and Interventional Cardiology Section, Division of Cardiology, BIDMC/Harvard Medical School, 330 Brookline Ave., Boston, MA 02215, USA.
Rosinberg
Audrey
A
Wykrzykowska
Joanna J
JJ
Shamis
Yulia
Y
Wu
Gui Fu
GF
Appelbaum
Evan
E
Li
Jian
J
Sellke
Frank W
FW
Pinto
Duane
D
Gibson
C Michael
CM
Mitrani
Eduardo
E
Laham
Roger J
RJ
D042501:Angiogenic Proteins / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002470:Cell Survival; D002908:Chronic Disease; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D062109:Dermatologic Surgical Procedures; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology; D008026:Ligation; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D018919:Neovascularization, Physiologic; D009924:Organ Culture Techniques; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D016038:Skin Transplantation; D013552:Swine; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D042501:Angiogenic Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents