Assessment of endogenous and therapeutic arteriogenesis by contrast ultrasound molecular imaging of integrin expression

Howard Leong-Poi, Jonathan Christiansen, Peter Heppner, Christopher W. Lewis, Alexander L. Klibanov, Sanjiv Kaul, Jonathan Lindner

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

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 αv- and α5β1-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 αv 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.

Original languageEnglish (US)
Pages (from-to)3248-3254
Number of pages7
JournalCirculation
Volume111
Issue number24
DOIs
StatePublished - Jun 21 2005
Externally publishedYes

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Molecular Imaging
Microbubbles
Integrins
Ultrasonography
Ligation
Fibroblast Growth Factor 2
Muscles
Iliac Artery
Oxygen
Ischemia
Disintegrins
Therapeutics
Perfusion Imaging
Arterioles
Hindlimb
Fluorescent Antibody Technique
Intercellular Signaling Peptides and Proteins
Extremities
Perfusion
Staining and Labeling

Keywords

  • Angiogenesis
  • Echocardiography
  • Ischemia
  • Peripheral vascular diseases
  • Ultrasonics

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Assessment of endogenous and therapeutic arteriogenesis by contrast ultrasound molecular imaging of integrin expression. / Leong-Poi, Howard; Christiansen, Jonathan; Heppner, Peter; Lewis, Christopher W.; Klibanov, Alexander L.; Kaul, Sanjiv; Lindner, Jonathan.

In: Circulation, Vol. 111, No. 24, 21.06.2005, p. 3248-3254.

Research output: Contribution to journalArticle

Leong-Poi, Howard ; Christiansen, Jonathan ; Heppner, Peter ; Lewis, Christopher W. ; Klibanov, Alexander L. ; Kaul, Sanjiv ; Lindner, Jonathan. / Assessment of endogenous and therapeutic arteriogenesis by contrast ultrasound molecular imaging of integrin expression. In: Circulation. 2005 ; Vol. 111, No. 24. pp. 3248-3254.
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AU - Leong-Poi, Howard

AU - Christiansen, Jonathan

AU - Heppner, Peter

AU - Lewis, Christopher W.

AU - Klibanov, Alexander L.

AU - Kaul, Sanjiv

AU - Lindner, Jonathan

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AB - 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 αv- and α5β1-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 αv 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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