Analysis of angiogenesis induced by local IGF-1 expression after myocardial infarction using microSPECT-CT imaging.
Insulin-like growth factor-1 (IGF-1) has been found to exert favorable effects on angiogenesis in prior animal studies. This study explored the long-term effect of IGF-1 on angiogenesis using microSPECT-CT in infarcted rat hearts after delivering human IGF-1 gene by adeno-associated virus (AAV). Myocardial infarction (MI) was induced in Sprague-Dawley rats by ligation of the proximal anterior coronary artery and a total of 10(11) AAV-CMV-lacZ (control) or IGF-1 vectors were injected around the peri-infarct area. IGF-1 expression by AAV stably transduced heart muscle for up to 16 weeks post-MI and immunohistochemistry revealed a remarkable increase in capillary density. A (99m)Tc-labeled RGD peptide (NC100692, GE Healthcare) was used to assess temporal and regional alpha(v) integrin activation. Rats were injected with NC100692 followed by (201)Tl chloride and in vivo microSPECT-CT imaging was performed. After imaging, hearts were excised and cut for quantitative gamma-well counting (GWC). NC100692 retention was significantly increased in hypoperfused regions of both lacZ and IGF-1 rats at 4 and 16 weeks post-MI. Significantly higher activation of alpha(v) integrin was observed in IGF-1 rats at 4 weeks after treatment compared with control group, although the activation was lower in the IGF-1 group at 16 weeks. Local IGF-1 gene delivery by AAV can render a sustained transduction and improve cardiac function post-MI. IGF-1 expression contributes to enhanced alpha(v) integrin activation which is linked to angiogenesis. MicroSPECT-CT imaging with (99m)Tc-NC100692 and quantitative GWC successfully assessed differences in alpha(v) integrin activation between IGF-1-treated and control animals post-MI.
Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8017, USA.
Lawrence W
LW
Dobrucki
Yoshiaki
Y
Tsutsumi
Leszek
L
Kalinowski
Jarrod
J
Dean
Mary
M
Gavin
Sabyasachi
S
Sen
Marivi
M
Mendizabal
Albert J
AJ
Sinusas
Ryuichi
R
Aikawa
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D039564:Integrin alphaV / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013667:Technetium / Q000494:pharmacology; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014057:Tomography, X-Ray Computed / Q000379:methods*
D039564:Integrin alphaV; D009842:Oligopeptides; D007334:Insulin-Like Growth Factor I; D013667:Technetium; C047981:arginyl-glycyl-aspartic acid