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Myoglobin overexpression inhibits reperfusion in the ischemic mouse hindlimb through impaired angiogenesis but not arteriogenesis.

ABSTRACT: Adaptive vascular remodeling in response to arterial occlusion takes the form of capillary growth (angiogenesis) and outward remodeling of pre-existing collateral arteries (arteriogenesis). However, the relative contributions of angiogenesis and arteriogenesis toward the overall reperfusion response are both highly debated and poorly understood. Here, we tested the hypothesis that myoglobin overexpressing transgenic mice (MbTg(+)) exhibit impaired angiogenesis in the setting of normal arteriogenesis in response to femoral artery ligation, and thereby serve as a model for disconnecting these two vascular growth processes. After femoral artery ligation, MbTg(+) mice were characterized by delayed distal limb reperfusion (by laser Doppler perfusion imaging), decreased foot use, and impaired distal limb muscle angiogenesis in both glycolytic and oxidative muscle fiber regions at day 7. Substantial arteriogenesis occurred in the primary collaterals supplying the ischemic limb in both wild-type and MbTg(+) mice; however, there were no significant differences between groups, indicating that myoglobin overexpression does not affect arteriogenesis. Together, these results uniquely demonstrate that functional collateral arteriogenesis alone is not necessarily sufficient for adequate reperfusion after arterial occlusion. Angiogenesis is a key component of an effective reperfusion response, and clinical strategies that target both angiogenesis and arteriogenesis could yield the most efficacious treatments for peripheral arterial disease.

SUBMITTER: Meisner JK

PROVIDER: S-EPMC5746951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Critical limb ischaemia (CLI), which is estimated to affect 2 million people in the United States, reduces quality of life, is associated with high morbidity and mortality, and has limited treatment options. Direct stimulation of angiogenesis using proangiogenic growth factors has been investigated as a therapeutic strategy to improve reperfusion in the ischaemic leg. Despite positive outcomes in animal studies, there has been little success in clinical translation. This investigation addressed the hypothesis that angiogenesis could be stimulated indirectly in the ischaemic hindlimb by blocking 11β-hydroxysteroid dehydrogenase 1 (11βHSD1)-mediated reactivation of anti-angiogenic glucocorticoids. Method and Results: Corticosterone suppressed ex vivo angiogenesis in the mouse aortic ring assay. 11βHSD1 deletion (Hsd11b1Del1/Del1) or pharmacological inhibition (with 300 nM UE2316) which block the reactivation of glucocorticoid (i.e., the conversion of 11-dehydrocorticosterone (11DHC) to bioactive corticosterone) significantly reduced 11DHC-induced suppression of angiogenesis. In a sponge implantation model, 11βHSD1 deletion, but not pharmacological inhibition, enhanced inflammation-induced angiogenesis. By contrast, in the mouse hindlimb ischaemia model, post-ischaemic reperfusion and vascular density were not affected by either deletion or pharmacological inhibition of 11βHSD1 in young or aged mice. 3D vascular imaging suggested that hind limb reperfusion in the 1st week following induction of ischaemia may be driven by the rapid expansion of collateral arteries rather than by angiogenesis. Conclusion: 11βHSD1-mediated glucocorticoid reactivation suppressed angiogenesis ex vivo and in vivo. However, regulation of angiogenesis alone was insufficient to promote reperfusion in hindlimb ischaemia. Future investigation of post-ischaemic reperfusion should include other aspects of systemic vascular remodeling including arteriogenesis and collateral formation.

Project description:ObjectiveThis study aimed to examine acellular extracellular matrix based hydrogels as potential therapies for treating peripheral artery disease (PAD). We tested the efficacy of using a tissue specific injectable hydrogel, derived from decellularized porcine skeletal muscle (SKM), compared to a new human umbilical cord derived matrix (hUC) hydrogel, which could have greater potential for tissue regeneration because of its young tissue source age.BackgroundThe prevalence of PAD is increasing and can lead to critical limb ischemia (CLI) with potential limb amputation. Currently there are no therapies for PAD that effectively treat all of the underlying pathologies, including reduced tissue perfusion and muscle atrophy.MethodsIn a rodent hindlimb ischemia model both hydrogels were injected 1-week post-surgery and perfusion was regularly monitored with laser speckle contrast analysis (LASCA) to 35 days post-injection. Histology and immunohistochemistry were used to assess neovascularization and muscle health. Whole transcriptome analysis was further conducted on SKM injected animals on 3 and 10 days post-injection.ResultsSignificant improvements in hindlimb tissue perfusion and perfusion kinetics were observed with both biomaterials. End point histology indicated this was a result of arteriogenesis, rather than angiogenesis, and that the materials were biocompatible. Skeletal muscle fiber morphology analysis indicated that the muscle treated with the tissue specific, SKM hydrogel more closely matched healthy tissue morphology. Short term histology also indicated arteriogenesis rather than angiogenesis, as well as improved recruitment of skeletal muscle progenitors. Whole transcriptome analysis indicated that the SKM hydrogel caused a shift in the inflammatory response, decreased cell death, and increased blood vessel and muscle development.ConclusionThese results show the efficacy of an injectable ECM hydrogel alone as a potential therapy for treating patients with PAD. Our results indicate that the SKM hydrogel improved functional outcomes through stimulation of arteriogenesis and muscle progenitor cell recruitment.

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Myoglobin overexpression inhibits reperfusion in the ischemic mouse hindlimb through impaired angiogenesis but not arteriogenesis.

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