Targeted in vivo extracellular matrix formation promotes neovascularization in a rodent model of myocardial infarction.
BACKGROUND
The extracellular matrix plays an important role in tissue regeneration. We investigated whether extracellular matrix protein fragments could be targeted with antibodies to ischemically injured myocardium to promote angiogenesis and myocardial repair.


RESULTS
Four peptides, 2 derived from fibronectin and 2 derived from Type IV Collagen, were assessed for in vitro and in vivo tendencies for angiogenesis. Three of the four peptides--Hep I, Hep III, RGD--were identified and shown to increase endothelial cell attachment, proliferation, migration and cell activation in vitro. By chemically conjugating these peptides to an anti-myosin heavy chain antibody, the peptides could be administered intravenously and specifically targeted to the site of the myocardial infarction. When administered into Sprague-Dawley rats that underwent ischemia-reperfusion myocardial infarction, these peptides produced statistically significantly higher levels of angiogenesis and arteriogenesis 6 weeks post treatment.


CONCLUSIONS
We demonstrated that antibody-targeted ECM-derived peptides alone can be used to sufficiently alter the extracellular matrix microenvironment to induce a dramatic angiogenic response in the myocardial infarct area. Our results indicate a potentially new non-invasive strategy for repairing damaged tissue, as well as a novel tool for investigating in vivo cell biology.
Mihardja
Shirley S
SS
Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.
Gao
Dongwei
D
Sievers
Richard E
RE
Fang
Qizhi
Q
Feng
Jinjin
J
Wang
Jianming
J
Vanbrocklin
Henry F
HF
Larrick
James W
JW
Huang
Manley
M
Dae
Michael
M
Lee
Randall J
RJ
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000627:therapeutic use; D024141:Collagen Type IV / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005109:Extracellular Matrix / Q000502:physiology*; D005353:Fibronectins / Q000737:chemistry; D018796:Immunoconjugates / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D018995:Myosin Heavy Chains / Q000276:immunology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D000906:Antibodies; D024141:Collagen Type IV; D005353:Fibronectins; D018796:Immunoconjugates; D010446:Peptide Fragments; D018995:Myosin Heavy Chains