Depressed expression of angiogenic growth factors in the subacute phase of myocardial ischemia: a mechanism behind the remodeling plateau?
OBJECTIVE
To investigate whether, in the subacute phase of acute myocardial infarction, in the peri-infarcted area the expressions of the vascular endothelial growth factor (VEGF-A) and angiopoietin (Ang) ligand receptors are depressed, and whether overexpression of these angiogens counteracts a downregulation of myocardial function.


METHODS
Acute myocardial infarction was induced by left anterior descending artery ligation and overexpression through injection of human VEGF-A165 and Ang-1 plasmids. The capillary and arteriolar densities, Akt-1 phosphorylation and citrate synthase activity were measured concurrent with the expression of VEGF-A, VEGFR1 and R2, Ang-1, Ang-2 and Tie-2.


RESULTS
One day after AMI, VEGR-2 was unchanged but all other measured factors in the two families were upregulated. After day 2, the Ang-2 expression increased but other measured factors decreased. After gene transfer, the vascular supply, Akt phosphorylation and citrate synthase activity were higher in the peri-infarcted area, where also the endogenous angiogenic growth factor expressions were increased.


CONCLUSIONS
A rapid decrease in angiogenic stimulating factors occurs in the subacute phase of AMI and is related to a progressive decrease in myocardial contraction. A negative consequence of such a circuit is a successive reduction in the vascular supply and contractility in areas with reduced perfusion. These negative adaptations can be counteracted by angiogen overexpression.
Siddiqui
Anwar Jewel
AJ
Department of Medicine, Division of Cardiology, Section of Integrative Physiology, Karolinska University Hospital, Karolinska Institutet, 141 86 Stockholm, Sweden. Anwar.J.Siddiqui@ki.se
Fischer
Helene
H
Widegren
Ulrika
U
Grinnemo
Karl-Henrik
KH
Hao
Xiaojin
X
Månsson-Broberg
Agneta
A
Sylvén
Christer
C
Gustafsson
Thomas
T
D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D042683:Angiopoietin-1 / Q000096:biosynthesis / Q000235:genetics; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D042787:Receptor, TIE-2; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D020257:Ventricular Remodeling
C467630:ANGPT1 protein, human; D042501:Angiogenic Proteins; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D002950:Citrate (si)-Synthase; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt