Four-Dimensional Microvascular Analysis Reveals That Regenerative Angiogenesis in Ischemic Muscle Produces a Flawed Microcirculation

Arpino, John‐Michael; Zhang, Nong; Li, Fuyan; Yin, Hao; Ghonaim, Nour; Milkovich, Stephanie; Balint, Brittany; O’Neil, Caroline; Fraser, Graham; Goldman, Daniel; Ellis, Christopher G.; Pickering, J. Geoffrey

doi:10.1161/circresaha.116.310535

Cited by 59 publications

(86 citation statements)

References 36 publications

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“…The capacity to recover muscle vascularization, as occurs with the HLI procedure, may not be equated with a full functional recovery of the muscle, especially in the presence of this regional (limb pair) balance. A recently published paper (Arpino et al 2017) supports the results from our model, reporting that the new microcirculatory network formed by regenerative angiogenesis in a skeletal muscle mouse model presented many structural and functional abnormalities even after several months. Reduced responsiveness in the operated limb is undoubtedly present due to the removal of the vessels, meaning that the non-operated limb responds more actively to the local (also to the central reflexes) effects of hyperoxia.…”

Section: Discussionsupporting

confidence: 88%

Observations on the perfusion recovery of regenerative angiogenesis in an ischemic limb model under hyperoxia

et al. 2018

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This study combines two well‐known vascular research models, hyperoxia and hind limb ischemia, aiming to better characterize capacities of the hyperoxia challenge. We studied two groups of C57/BL6 male mice, a control (C) and a hind limb ischemia (HLI) group. Perfusion from both limbs was recorded in all animals by laser Doppler techniques under an oxygen (O2) saturated atmosphere, once for control and, during 35 days for the HLI group. We used a third set of normoxic animals for HLI morphometric control. The expected variability of responses was higher for the younger animals. In the HLI group, capillary density normalized at Day 21 as expected, but not microcirculatory physiology. In the operated limb, perfusion decreased dramatically following surgery (Day 4), as a slight reduction in the non‐operated limb was also noted. Consistently, the response to hyperoxia was an increased perfusion in the ischemic limb and decreased perfusion in the contralateral limb. Only at Day 35, both limbs exhibited similar flows, although noticeably lower than Day 0. These observations help to understand some of the functional variability attributed to the hyperoxia model, by showing (i) differences in the circulation of the limb pairs to readjust a new perfusion set‐point even after ischemia, an original finding implying that (ii) data from both limbs should be recorded when performing distal measurements in vivo. Our data demonstrate that the new vessels following HLI are not functionally normal, and this also affects the non‐operated limb. These findings confirm the discriminative capacities of the hyperoxia challenge and suggest its potential utility to study other pathologies with vascular impact.

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Section: Discussionsupporting

confidence: 88%

Observations on the perfusion recovery of regenerative angiogenesis in an ischemic limb model under hyperoxia

et al. 2018

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“…Recent reports of pathologic vessel patterning in regenerated vascular networks after HLI could clarify the Arnt SMKO reperfusion deficit. Arpino et al implicated disordered VSMC phenotype and wrapping around small arterioles in limiting red blood cell transit through the microvasculature of regenerating skeletal muscle . Similarly, in skeletal muscle of Arnt SMKO mice, we detect aberrant smooth muscle cell morphologic features and investment of the small arterioles, consistent with these novel reports.…”

Section: Discussionsupporting

confidence: 90%

“…Arpino et al implicated disordered VSMC phenotype and wrapping around small arterioles in limiting red blood cell transit through the microvasculature of regenerating skeletal muscle. 44 Similarly, in skeletal muscle of Arnt SMKO mice, we detect aberrant smooth muscle cell morphologic features and investment of the small arterioles, consistent with these novel reports. Furthermore, the integrity of the microvasculature is compromised, as evidenced by increased permeability.…”

Section: Discussionsupporting

confidence: 89%

Aryl Hydrocarbon Receptor Nuclear Translocator in Vascular Smooth Muscle Cells Is Required for Optimal Peripheral Perfusion Recovery

Borton

Benson

Neilson

et al. 2018

JAHA

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BackgroundLimb ischemia resulting from peripheral vascular disease is a common cause of morbidity. Vessel occlusion limits blood flow, creating a hypoxic environment that damages distal tissue, requiring therapeutic revascularization. Hypoxia‐inducible factors (HIFs) are key transcriptional regulators of hypoxic vascular responses, including angiogenesis and arteriogenesis. Despite vascular smooth muscle cells’ (VSMCs’) importance in vessel integrity, little is known about their functional responses to hypoxia in peripheral vascular disease. This study investigated the role of VSMC HIF in mediating peripheral ischemic responses.Methods and ResultsWe used Arnt SMKO mice with smooth muscle–specific deletion of aryl hydrocarbon receptor nuclear translocator (ARNT, HIF‐1β), required for HIF transcriptional activity, in a femoral artery ligation model of peripheral vascular disease. Arnt SMKO mice exhibit impaired perfusion recovery despite normal collateral vessel dilation and angiogenic capillary responses. Decreased blood flow manifests in extensive tissue damage and hypoxia in ligated limbs of Arnt SMKO mice. Furthermore, loss of aryl hydrocarbon receptor nuclear translocator changes the proliferation, migration, and transcriptional profile of cultured VSMCs. Arnt SMKO mice display disrupted VSMC morphologic features and wrapping around arterioles and increased vascular permeability linked to decreased local blood flow.ConclusionsOur data demonstrate that traditional vascular remodeling responses are insufficient to provide robust peripheral tissue reperfusion in Arnt SMKO mice. In all, this study highlights HIF responses to hypoxia in arteriole VSMCs critical for the phenotypic and functional stability of vessels that aid in the recovery of blood flow in ischemic peripheral tissues.

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“…Although the molecular control of intussusceptive angiogenesis is less well understood, this process can dramatically modify the microcirculation by pruning or duplicating vessels creating an organ specific angioarchitecture. Highly studied in the context of tissue ischemia and tumor biology , angiogenesis is best envisioned as a dynamic process of microvessel advancement and regression to increase capillary density.…”

Section: Stem and Progenitor Cells That Govern Vascular Regenerationmentioning

confidence: 99%

Concise Review: Cell Therapy for Critical Limb Ischemia: An Integrated Review of Preclinical and Clinical Studies

et al. 2018

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Critical limb ischemia (CLI), the most severe form of peripheral artery disease, is characterized by pain at rest and non-healing ulcers in the lower extremities. For patients with CLI, where the extent of atherosclerotic artery occlusion is too severe for surgical bypass or percutaneous interventions, limb amputation remains the only treatment option. Thus, cell-based therapy to restore perfusion and promote wound healing in patients with CLI is under intense investigation. Despite promising preclinical studies in animal models, transplantation of bone marrow (BM)-derived cell populations in patients with CLI has shown limited benefit preventing limb amputation. Early trials injected heterogenous mononuclear cells containing a low frequency of cells with pro-vascular regenerative functions. Most trials transferred autologous cells damaged by chronic disease that demonstrated poor survival in the ischemic environment and impaired function conferred by atherosclerotic or diabetic co-morbidities. Finally, recent preclinical studies suggest optimized blood vessel formation may require paracrine and/or structural contributions from multiple progenitor cell lineages, angiocrine-secretory myeloid cells derived from hematopoietic progenitor cells, tubule-forming endothelial cells generated by circulating or vessel-resident endothelial precursors, and vessel-stabilizing perivascular cells derived from mesenchymal stem cells. Understanding how stem cells co-ordinate the myriad of cells and signals required for stable revascularization remains the key to translating the potential of stem cells into curative therapies for CLI. Thus, combination delivery of multiple cell types within supportive bioengineered matricies may represent a new direction to improve cell therapy strategies for CLI. Stem Cells 2018;36:161-171.

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Four-Dimensional Microvascular Analysis Reveals That Regenerative Angiogenesis in Ischemic Muscle Produces a Flawed Microcirculation

Cited by 59 publications

References 36 publications

Observations on the perfusion recovery of regenerative angiogenesis in an ischemic limb model under hyperoxia

Observations on the perfusion recovery of regenerative angiogenesis in an ischemic limb model under hyperoxia

Aryl Hydrocarbon Receptor Nuclear Translocator in Vascular Smooth Muscle Cells Is Required for Optimal Peripheral Perfusion Recovery

Concise Review: Cell Therapy for Critical Limb Ischemia: An Integrated Review of Preclinical and Clinical Studies

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