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Repetitive remote occlusion (RRO) stimulates eNOS-dependent blood flow and collateral expansion in hindlimb ischemia

Schuler, Dominik, Sansone, Roberto, Nicolaus, Christopher, Kelm, Malte and Heiss, Christian (2018) Repetitive remote occlusion (RRO) stimulates eNOS-dependent blood flow and collateral expansion in hindlimb ischemia Free Radical Biology and Medicine, 129. pp. 520-531.

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Arteriogenesis 10.09.2018_V17R1-Final Clean.docx - Accepted version Manuscript

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Collateral expansion is an important compensatory mechanism to alleviate tissue ischemia after arterial occlusion. We investigated the efficacy and mechanisms of temporary remote hindlimb occlusion to stimulate contralateral blood flow and collateral expansion after hindlimb ischemia in mice and evaluated translation to peripheral artery disease in humans.

Methods and Results:

We induced unilateral hindlimb ischemia via femoral artery excision in mice. We studied central hemodynamics, blood flow, and perfusion of the ischemic hindlimb during single and repetitive remote occlusion (RRO) of the contralateral non-ischemic hindlimb with a pressurized cuff. Similar experiments were performed in patients with unilateral peripheral artery disease (PAD). Contralateral occlusion of the non-ischemic hindlimb led to an acute increase in blood flow to the ischemic hindlimb without affecting central blood pressure and cardiac output. The increase in blood flow was sustained even after deflation of the pressure cuff. RRO over 12 days (8/day, each 5 min) led to significantly increased arterial inflow, lumen expansion of collateral arteries, and increased perfusion of the chronically ischemic hindlimb as compared to control. In NOS3-/- and after inhibition of NOS (L-NAME), and NO (ODQ), the acute and chronic effects of contralateral occlusion were abrogated and stimulation of guanylyl cyclase with cinaciguate exhibited a similar response as RRO and was not additive. Pilot studies in PAD patients demonstrated that contralateral occlusion increased arterial inflow to ischemic limbs and improved walking distance.


Repetitive remote contralateral occlusion stimulates arterial inflow, perfusion, and functional collateral expansion in chronic hindlimb ischemia via an eNOS-dependent mechanism underscoring the potential of remote occlusion as a novel treatment option in peripheral artery disease.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Schuler, Dominik
Sansone, Roberto
Nicolaus, Christopher
Kelm, Malte
Date : 15 October 2018
DOI : 10.1016/j.freeradbiomed.2018.10.399
Copyright Disclaimer : © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Uncontrolled Keywords : endothelial nitric oxide synthase; ischemia; shear stress; collateral circulation; peripheral artery disease
Depositing User : Melanie Hughes
Date Deposited : 03 Oct 2018 13:52
Last Modified : 16 Oct 2019 02:08

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