Trans-illuminated laser speckle imaging of collateral artery blood flow in ischemic mouse hindlimb

Meisner, Joshua K.; Niu, Jacqueline; Sumer, Suna; Price, Richard J.

doi:10.1117/1.jbo.18.9.096011

Cited by 14 publications

(26 citation statements)

References 33 publications

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“…Using transillumination laser speckle flowmetry (LSF), we recently determined that shear stress magnitude increases 2-fold in both the muscular and saphenous collateral entrance regions 30 minutes post-FAL. Additionally, we confirmed the predicted flow directions in this ligation scheme through observation of circulating fluorescent microspheres during intravital imaging 18 .…”

Section: Resultssupporting

confidence: 73%

“…Femoral arterial ligation (FAL), performed as previously described 18 , was used to induce arteriogenesis in the gracilis adductor muscle collateral arteries. In agreement with previous studies 19,20 , perfusion measurements of the plantar surface of the foot indicated moderate ischemia immediately post-FAL, followed by a return to full perfusion by day 7 post-FAL (Supplemental Figure I).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we applied transillumination based laser speckle flowmetry (LSF) to quantify, for the first time, the in-vivo “segment-to-segment” spatial distribution of collateral artery hemodynamics before and after femoral artery ligation in the mouse ischemic hindlimb, the most widely used model of peripheral arteriogenesis. While shear stress magnitude increased ~2-fold along the length of the collateral vessels in the gracilis adductor muscle, some pre-existing collateral artery segments also experienced a reversal of flow direction after femoral artery ligation 18 . In the present study, we tested the hypothesis that a change in flow direction has a profound influence on both arteriogenesis and mechanotransductive endothelial cell signaling.…”

Section: Introductionmentioning

confidence: 98%

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Mechanisms of Amplified Arteriogenesis in Collateral Artery Segments Exposed to Reversed Flow Direction

Heuslein

Meisner

et al. 2015

ATVB

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Objective Collateral arteriogenesis, the growth of existing arterial vessels to a larger diameter, is a fundamental adaptive response that is often critical for the perfusion and survival of tissues downstream of chronic arterial occlusion(s). Shear stress regulates arteriogenesis; however, the arteriogenic significance of flow direction reversal, occurring in numerous collateral artery segments after femoral artery ligation (FAL), is unknown. Our objective was to determine if flow direction reversal in collateral artery segments differentially regulates endothelial cell signaling and arteriogenesis. Approach and Results Collateral segments experiencing flow reversal after FAL in C57BL/6 mice exhibit increased pericollateral macrophage recruitment, amplified arteriogenesis (30% diameter and 2.8-fold conductance increases), and remarkably permanent (12 weeks post-FAL) remodeling. Genome-wide transcriptional analyses on HUVECs exposed to flow reversal conditions mimicking those occurring in-vivo yielded 10-fold more significantly regulated transcripts, as well as enhanced activation of upstream regulators (NFκB, VEGF, FGF2, TGFβ) and arteriogenic canonical pathways (PKA, PDE, MAPK). Augmented expression of key pro-arteriogenic molecules (KLF2, ICAM-1, eNOS) was also verified by qRT-PCR, leading us to test whether ICAM-1 and/or eNOS regulate amplified arteriogenesis in flow-reversed collateral segments in-vivo. Interestingly, enhanced pericollateral macrophage recruitment and amplified arteriogenesis was attenuated in flow-reversed collateral segments after FAL in ICAM-1−/− mice; however, eNOS−/− mice showed no such differences. Conclusions Flow reversal leads to a broad amplification of pro-arteriogenic endothelial signaling and a sustained ICAM-1-dependent augmentation of arteriogenesis. Further investigation of the endothelial mechanotransduction pathways activated by flow reversal may lead to more effective and durable therapeutic options for arterial occlusive diseases.

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Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Mechanisms of Amplified Arteriogenesis in Collateral Artery Segments Exposed to Reversed Flow Direction

Heuslein

Meisner

et al. 2015

ATVB

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“…A cone and plate flow apparatus, 82 which maintains cells at 5% CO 2 and 37°C, was used to induce a shear stress protocol. The applied shear stress protocol consisted of a 24-hr preconditioning period at a steady 15 dyne/cm 2 , which was then either increased to 30 dynes/cm 2 (non-reversed flow) or increased to 30 dynes/cm 2 and reversed in direction (reversed flow) to simulate relative hemodynamics previously quantified in our in vivo FAL model 11 . Fresh culture medium, consisting of M199 with 4% dextran from Leuconostoc spp (Sigma-Aldrich, M r ∼500,000), 2% fetal bovine serum, 100 U/mL penicillin-G + 100 μg/mL streptomycin, 2 mmol/L L-glutamine, 5 μg/mL EC growth supplement, and 10 μg/mL heparin, was added to cells before exposure to shear stress, and it was continuously exchanged throughout the duration in the cone and plate apparatus.…”

Section: Methodsmentioning

confidence: 99%

Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis

Heuslein

Gorick

McDonnell

et al. 2018

Molecular Therapy - Nucleic Acids

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Arteriogenesis, the growth of endogenous collateral arteries bypassing arterial occlusion(s), is a fundamental shear stress-induced adaptation with implications for treating peripheral arterial disease (PAD). Nonetheless, endothelial mechano-signaling during arteriogenesis is incompletely understood. Here we tested the hypothesis that a mechanosensitive microRNA, miR-199a-5p, regulates perfusion recovery and collateral arteriogenesis following femoral arterial ligation (FAL) via control of monocyte recruitment and pro-arteriogenic gene expression. We have previously shown that collateral artery segments exhibit distinctly amplified arteriogenesis if they are exposed to reversed flow following FAL in the mouse. We performed a genome-wide analysis of endothelial cells exposed to a biomimetic reversed flow waveform. From this analysis, we identified mechanosensitive miR-199a-5p as a novel candidate regulator of collateral arteriogenesis. In vitro, miR-199a-5p inhibited pro-arteriogenic gene expression (IKKβ, Cav1) and monocyte adhesion to endothelium. In vivo, following FAL in mice, miR-199a-5p overexpression impaired foot perfusion and arteriogenesis. In contrast, a single intramuscular anti-miR-199a-5p injection elicited a robust therapeutic response, including complete foot perfusion recovery, markedly augmented arteriogenesis (>3.4-fold increase in segment conductance), and improved gastrocnemius tissue composition. Finally, we found plasma miR-199a-5p to be elevated in human PAD patients with intermittent claudication compared to a risk factor control population. Through our transformative analysis of endothelial mechano-signaling in response to a biomimetic amplified arteriogenesis flow waveform, we have identified miR-199a-5p as both a potent regulator of arteriogenesis and a putative target for treating PAD.

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“…Assuming Lorentzian velocity distribution, ðK s Þ 2 is inversely proportional to the blood flow velocity (motion of scattering particles), such that lower speed results in higher K S and vice versa. [86][87][88] For instance, K s is close to unity if there is no movement within the medium. Concomitant to flow measurements, temporal changes in concentrations of the brain metabolism biomarkers oxyhemoglobin (ΔHbO 2 ) and deoxyhemoglobin (ΔHbr) can be extracted from the diffuse reflectance data by the Beer-Lambert method.…”

mentioning

confidence: 99%

Noninvasive assessment of hemodynamic and brain metabolism parameters following closed head injury in a mouse model by comparative diffuse optical reflectance approaches

et al. 2016

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Abstract. Optical techniques have gained substantial interest over the past four decades for biomedical imaging due to their unique advantages, which may suggest their use as alternatives to conventional methodologies. Several optical techniques have been successfully adapted to clinical practice and biomedical research to monitor tissue structure and function in both humans and animal models. This paper reviews the analysis of the optical properties of brain tissue in the wavelength range between 500 and 1000 nm by three different diffuse optical reflectance methods: spatially modulated illumination, orthogonal diffuse light spectroscopy, and dualwavelength laser speckle imaging, to monitor changes in brain tissue morphology, chromophore content, and metabolism following head injury. After induction of closed head injury upon anesthetized mice by weight-drop method, significant changes in hemoglobin oxygen saturation, blood flow, and metabolism were readily detectible by all three optical setups, up to 1 h post-trauma. Furthermore, the experimental results clearly demonstrate the feasibility and reliability of the three methodologies, and the differences between the system performances and capabilities are also discussed. The long-term goal of this line of study is to combine these optical systems to study brain pathophysiology in high spatiotemporal resolution using additional models of brain trauma. Such combined use of complementary algorithms should fill the gaps in each system's capabilities, toward the development of a noninvasive, quantitative tool to expand our knowledge of the principles underlying brain function following trauma, and to monitor the efficacy of therapeutic interventions in the clinic.

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Trans-illuminated laser speckle imaging of collateral artery blood flow in ischemic mouse hindlimb

Cited by 14 publications

References 33 publications

Mechanisms of Amplified Arteriogenesis in Collateral Artery Segments Exposed to Reversed Flow Direction

Mechanisms of Amplified Arteriogenesis in Collateral Artery Segments Exposed to Reversed Flow Direction

Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis

Noninvasive assessment of hemodynamic and brain metabolism parameters following closed head injury in a mouse model by comparative diffuse optical reflectance approaches

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