Journal
CIRCULATION
Volume 111, Issue 24, Pages 3248-3254Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.104.481515
Keywords
angiogenesis; echocardiography; ischemia; peripheral vascular diseases; ultrasonics
Funding
- NHLBI NIH HHS [R01-HL-078610, R01-HL-074443] Funding Source: Medline
- NIBIB NIH HHS [R01-EB-002069] Funding Source: Medline
- NIDDK NIH HHS [R01-DK-063508] Funding Source: Medline
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Background - We hypothesized that molecular imaging with contrast- enhanced ultrasound ( CEU) and microbubbles targeted to endothelial integrins could be used to noninvasively assess early angiogenic responses to ischemia and growth factor therapy. Methods and Results - Hindlimb ischemia was produced in 48 rats by ligation of an iliac artery. Half of the animals received intramuscular sustained- release fibroblast growth factor- 2 ( FGF- 2). Immediately after ligation and at subsequent intervals from 4 to 28 days, blood flow and oxygen tension in the proximal adductor muscles were measured by CEU perfusion imaging and phosphor quenching, respectively. Targeted CEU imaging of alpha(v)- and alpha(5)beta(1)- integrin expression was performed with microbubbles bearing the disintegrin echistatin. Iliac artery ligation produced a 65% to 70% reduction in blood flow and oxygen tension. In untreated ischemic muscle, muscle flow and oxygen tension partially recovered by days 14 to 28. In these animals, signal from integrin- targeted microbubbles was intense and peaked before flow increase ( days 4 to 7). In comparison to untreated animals, FGF- 2 - treated muscle had a greater rate and extent of blood flow recovery and greater signal intensity from integrin- targeted microbubbles, which peaked before maximal recovery of flow. On immunohistology, arteriolar but not capillary density increased in the ischemic limb after ligation, the rate and degree of which were greater in FGF- 2 - treated rats. Immunofluorescence demonstrated intense staining for alpha(v) in arterioles, the temporal course of which correlated with targeted imaging. Conclusions - Targeted CEU can be used to assess endogenous and therapeutic arteriogenesis before recovery of tissue perfusion. These results suggest that molecular imaging of integrin expression may be useful for evaluating proangiogenic therapies.
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