A Functional Murine Model of Hindlimb Demand Ischemia

Michael A. Peck, Robert S. Crawford, Christopher J. Abularrage, Virendra I. Patel, Mark F. Conrad, Jin Hyung Yoo, Michael T. Watkins, Hassan Albadawi

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: To date, murine models of treadmill exercise have been used to study general exercise physiology and angiogenesis in ischemic hindlimbs. The purpose of these experiments was to develop a murine model of demand ischemia in an ischemic limb to mimic claudication in humans. The primary goal was to determine whether treadmill exercise reflected a hemodynamic picture which might be consistent with the hyperemic response observed in humans. Methods: Aged hypercholesterolemic ApoE null mice (ApoE-/-, n = 13) were subjected to femoral artery ligation (FAL) and allowed to recover from the acute ischemic response. Peripheral perfusion of the hindlimbs at rest was determined by serial evaluation using laser Doppler imaging (LDI) on days 0, 7, and 14 following FAL. During the experiments, mice were also assessed on an established five-point clinical ischemic score, which assessed the degree of digital amputation, necrosis, and cyanosis compared to the nonischemic contralateral limb. After stabilization of the LDI ratio (ischemic limb flux/contralateral nonischemic limb flux) and clinical ischemic score, mice underwent 2 days of treadmill training (10 min at 10 m/min, incline of 10°) followed by 60 min of daily treadmill exercise (13 m/min, incline of 10°) through day 25. An evaluation of preexercise and postexercise perfusion using LDI was performed on two separate occasions following the onset of daily exercise. During the immediate 15 min postexercise evaluation, LDI scanning was obtained in quadruplicate, to allow identification of peak flux ratios. Statistical analysis included unpaired t-tests and analysis of variance. Results: After FAL, the LDI flux ratio reached a nadir between days 1 and 2, then stabilized by day 14 and remained stable through day 25. The clinical ischemic score stabilized at day 7 and remained stable throughout the rest of the experiment. Based on stabilization of both the clinical ischemic score and LDI ratio, exercise training began on day 15. The peak 15 min postexercise LDI ratio increased significantly compared to the preexercise ratio on day 17 (0.48 ± 0.04 vs. 0.34 ± 0.04, p < 0.05) and day 25 (0.37 ± 0.03 vs. 0.27 ± 0.03, p < 0.01). Within 2 hr of exercise, the LDI ratio returned to preexercise levels on both days 17 and 25. Conclusion: Clinical and hemodynamic stabilization of limb perfusion is evident by 14 days after FAL. FAL followed by demand ischemia results in a reversible relative hyperemic response similar to that observed in exercising human claudicants. A murine model of FAL associated with demand ischemia may be useful to evaluate the metabolic, inflammatory, and flow-related changes associated with claudication in humans.

Original languageEnglish (US)
Pages (from-to)532-537
Number of pages6
JournalAnnals of Vascular Surgery
Volume24
Issue number4
DOIs
StatePublished - May 1 2010
Externally publishedYes

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Hindlimb
Lasers
Femoral Artery
Ischemia
Ligation
Extremities
Perfusion
Apolipoproteins E
Hemodynamics
Cyanosis
Amputation
Analysis of Variance
Necrosis
Exercise

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Peck, M. A., Crawford, R. S., Abularrage, C. J., Patel, V. I., Conrad, M. F., Yoo, J. H., ... Albadawi, H. (2010). A Functional Murine Model of Hindlimb Demand Ischemia. Annals of Vascular Surgery, 24(4), 532-537. https://doi.org/10.1016/j.avsg.2009.12.003

A Functional Murine Model of Hindlimb Demand Ischemia. / Peck, Michael A.; Crawford, Robert S.; Abularrage, Christopher J.; Patel, Virendra I.; Conrad, Mark F.; Yoo, Jin Hyung; Watkins, Michael T.; Albadawi, Hassan.

In: Annals of Vascular Surgery, Vol. 24, No. 4, 01.05.2010, p. 532-537.

Research output: Contribution to journalArticle

Peck, MA, Crawford, RS, Abularrage, CJ, Patel, VI, Conrad, MF, Yoo, JH, Watkins, MT & Albadawi, H 2010, 'A Functional Murine Model of Hindlimb Demand Ischemia', Annals of Vascular Surgery, vol. 24, no. 4, pp. 532-537. https://doi.org/10.1016/j.avsg.2009.12.003
Peck MA, Crawford RS, Abularrage CJ, Patel VI, Conrad MF, Yoo JH et al. A Functional Murine Model of Hindlimb Demand Ischemia. Annals of Vascular Surgery. 2010 May 1;24(4):532-537. https://doi.org/10.1016/j.avsg.2009.12.003
Peck, Michael A. ; Crawford, Robert S. ; Abularrage, Christopher J. ; Patel, Virendra I. ; Conrad, Mark F. ; Yoo, Jin Hyung ; Watkins, Michael T. ; Albadawi, Hassan. / A Functional Murine Model of Hindlimb Demand Ischemia. In: Annals of Vascular Surgery. 2010 ; Vol. 24, No. 4. pp. 532-537.
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abstract = "Background: To date, murine models of treadmill exercise have been used to study general exercise physiology and angiogenesis in ischemic hindlimbs. The purpose of these experiments was to develop a murine model of demand ischemia in an ischemic limb to mimic claudication in humans. The primary goal was to determine whether treadmill exercise reflected a hemodynamic picture which might be consistent with the hyperemic response observed in humans. Methods: Aged hypercholesterolemic ApoE null mice (ApoE-/-, n = 13) were subjected to femoral artery ligation (FAL) and allowed to recover from the acute ischemic response. Peripheral perfusion of the hindlimbs at rest was determined by serial evaluation using laser Doppler imaging (LDI) on days 0, 7, and 14 following FAL. During the experiments, mice were also assessed on an established five-point clinical ischemic score, which assessed the degree of digital amputation, necrosis, and cyanosis compared to the nonischemic contralateral limb. After stabilization of the LDI ratio (ischemic limb flux/contralateral nonischemic limb flux) and clinical ischemic score, mice underwent 2 days of treadmill training (10 min at 10 m/min, incline of 10°) followed by 60 min of daily treadmill exercise (13 m/min, incline of 10°) through day 25. An evaluation of preexercise and postexercise perfusion using LDI was performed on two separate occasions following the onset of daily exercise. During the immediate 15 min postexercise evaluation, LDI scanning was obtained in quadruplicate, to allow identification of peak flux ratios. Statistical analysis included unpaired t-tests and analysis of variance. Results: After FAL, the LDI flux ratio reached a nadir between days 1 and 2, then stabilized by day 14 and remained stable through day 25. The clinical ischemic score stabilized at day 7 and remained stable throughout the rest of the experiment. Based on stabilization of both the clinical ischemic score and LDI ratio, exercise training began on day 15. The peak 15 min postexercise LDI ratio increased significantly compared to the preexercise ratio on day 17 (0.48 ± 0.04 vs. 0.34 ± 0.04, p < 0.05) and day 25 (0.37 ± 0.03 vs. 0.27 ± 0.03, p < 0.01). Within 2 hr of exercise, the LDI ratio returned to preexercise levels on both days 17 and 25. Conclusion: Clinical and hemodynamic stabilization of limb perfusion is evident by 14 days after FAL. FAL followed by demand ischemia results in a reversible relative hyperemic response similar to that observed in exercising human claudicants. A murine model of FAL associated with demand ischemia may be useful to evaluate the metabolic, inflammatory, and flow-related changes associated with claudication in humans.",
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N2 - Background: To date, murine models of treadmill exercise have been used to study general exercise physiology and angiogenesis in ischemic hindlimbs. The purpose of these experiments was to develop a murine model of demand ischemia in an ischemic limb to mimic claudication in humans. The primary goal was to determine whether treadmill exercise reflected a hemodynamic picture which might be consistent with the hyperemic response observed in humans. Methods: Aged hypercholesterolemic ApoE null mice (ApoE-/-, n = 13) were subjected to femoral artery ligation (FAL) and allowed to recover from the acute ischemic response. Peripheral perfusion of the hindlimbs at rest was determined by serial evaluation using laser Doppler imaging (LDI) on days 0, 7, and 14 following FAL. During the experiments, mice were also assessed on an established five-point clinical ischemic score, which assessed the degree of digital amputation, necrosis, and cyanosis compared to the nonischemic contralateral limb. After stabilization of the LDI ratio (ischemic limb flux/contralateral nonischemic limb flux) and clinical ischemic score, mice underwent 2 days of treadmill training (10 min at 10 m/min, incline of 10°) followed by 60 min of daily treadmill exercise (13 m/min, incline of 10°) through day 25. An evaluation of preexercise and postexercise perfusion using LDI was performed on two separate occasions following the onset of daily exercise. During the immediate 15 min postexercise evaluation, LDI scanning was obtained in quadruplicate, to allow identification of peak flux ratios. Statistical analysis included unpaired t-tests and analysis of variance. Results: After FAL, the LDI flux ratio reached a nadir between days 1 and 2, then stabilized by day 14 and remained stable through day 25. The clinical ischemic score stabilized at day 7 and remained stable throughout the rest of the experiment. Based on stabilization of both the clinical ischemic score and LDI ratio, exercise training began on day 15. The peak 15 min postexercise LDI ratio increased significantly compared to the preexercise ratio on day 17 (0.48 ± 0.04 vs. 0.34 ± 0.04, p < 0.05) and day 25 (0.37 ± 0.03 vs. 0.27 ± 0.03, p < 0.01). Within 2 hr of exercise, the LDI ratio returned to preexercise levels on both days 17 and 25. Conclusion: Clinical and hemodynamic stabilization of limb perfusion is evident by 14 days after FAL. FAL followed by demand ischemia results in a reversible relative hyperemic response similar to that observed in exercising human claudicants. A murine model of FAL associated with demand ischemia may be useful to evaluate the metabolic, inflammatory, and flow-related changes associated with claudication in humans.

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