Tissue-engineered pro-angiogenic fibroblast scaffold improves myocardial perfusion and function and limits ventricular remodeling after infarction.
OBJECTIVE
Microvascular malperfusion after myocardial infarction leads to infarct expansion, adverse remodeling, and functional impairment. Native reparative mechanisms exist but are inadequate to vascularize ischemic myocardium. We hypothesized that a 3-dimensional human fibroblast culture (3DFC) functions as a sustained source of angiogenic cytokines, thereby augmenting native angiogenesis and limiting adverse effects of myocardial ischemia.


METHODS
Lewis rats underwent ligation of the left anterior descending coronary artery to induce heart failure; experimental animals received a 3DFC scaffold to the ischemic region. Border-zone tissue was analyzed for the presence of human fibroblast surface protein, vascular endothelial growth factor, and hepatocyte growth factor. Cardiac function was assessed with echocardiography and pressure-volume conductance. Hearts underwent immunohistochemical analysis of angiogenesis by co-localization of platelet endothelial cell adhesion molecule and alpha smooth muscle actin and by digital analysis of ventricular geometry. Microvascular angiography was performed with fluorescein-labeled lectin to assess perfusion.


RESULTS
Immunoblotting confirmed the presence of human fibroblast surface protein in rats receiving 3DFC, indicating survival of transplanted cells. Increased expression of vascular endothelial growth factor and hepatocyte growth factor in experimental rats confirmed elution by the 3DFC. Microvasculature expressing platelet endothelial cell adhesion molecule/alpha smooth muscle actin was increased in infarct and border-zone regions of rats receiving 3DFC. Microvascular perfusion was also improved in infarct and border-zone regions in these rats. Rats receiving 3DFC had increased wall thickness, smaller infarct area, and smaller infarct fraction. Echocardiography and pressure-volume measurements showed that cardiac function was preserved in these rats.


CONCLUSIONS
Application of a bioengineered 3DFC augments native angiogenesis through delivery of angiogenic cytokines to ischemic myocardium. This yields improved microvascular perfusion, limits infarct progression and adverse remodeling, and improves ventricular function.
Fitzpatrick
J Raymond
JR
Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
Frederick
John R
JR
McCormick
Ryan C
RC
Harris
David A
DA
Kim
Ah-Young
AY
Muenzer
Jeffrey R
JR
Gambogi
Alex J
AJ
Liu
Jing Ping
JP
Paulson
E Carter
EC
Woo
Y Joseph
YJ
D042501:Angiogenic Proteins / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D003326:Coronary Circulation; D004195:Disease Models, Animal; D004452:Echocardiography; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation*; D006439:Hemodynamics; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D008833:Microcirculation; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D042501:Angiogenic Proteins; C066855:HGF protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor