Low-flow intussusception and metastable VEGFR2 signaling launch angiogenesis in ischemic muscle

Arpino, John‐Michael; Yin, Hao; Prescott, Emma; Staples, Sabrina C. R.; Zhang, Nong; Li, Fuyan; Chevalier, Jacqueline; Balint, Brittany; O’Neil, Caroline; Mortuza, Rokhsana; Milkovich, Stephanie; Lee, Jason J.; Lorusso, Daniel; Sandig, Martin; Hamilton, David A.; Holdsworth, David W.; Poepping, Tamie L.; Ellis, Christopher G.; Pickering, J. Geoffrey

doi:10.1126/sciadv.abg9509

Cited by 13 publications

(10 citation statements)

References 66 publications

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“…2C&D). This mechanism of revascularization was recently reported to be the dominant mechanism of regenerative angiogenesis following hindlimb ischemia ( 15 ). Through 14 dpi, microvessels would split into two daughter vessels and thereby generate numerous branches with short interconnections and without associated sprouting points (Fig.…”

Section: Main Textmentioning

confidence: 84%

“…2) by forming pillars within the lumen of a vessel that extend to split a preexisting vessel into two daughter segments and modify branch angles at bifurcations (37). During regeneration following hindlimb ischemia in mice, intussusception was the dominant mechanism of angiogenesis (38). The findings presented herein illustrate that both sprouting and intussusceptive angiogenesis contribute to microvascular regeneration following punch biopsy injury.…”

Section: Discussionmentioning

confidence: 99%

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Angiogenesis precedes myogenesis during regeneration following biopsy injury in skeletal muscle

Jacobsen

Morton

Segal

2022

Preprint

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Acute injury to skeletal muscle damages myofibers and fragments capillaries which then regenerate to restore intact muscle. However, it is unknown whether these processes are concomitant or proceed sequentially. We find that following punch biopsy of skeletal muscle in adult mice, which removes all tissue components, a provisional matrix fills the wound within 1 day post injury (dpi). Microvessels infiltrate the matrix by 7 dpi, with perfused networks traversing the wound by 14 dpi. In contrast, the wound is devoid of myofibers at 7 dpi. Myofibers begin regenerating into the wound at 14 dpi and span the wound by 21 dpi. We conclude that angiogenesis precedes myogenesis following skeletal muscle biopsy injury and suggest that a vascular supply supports myofiber regeneration.

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Section: Main Textmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Angiogenesis precedes myogenesis during regeneration following biopsy injury in skeletal muscle

Jacobsen

Morton

Segal

2022

Preprint

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“…These systems provide easily accessible, standardized conditions with spatiotemporal control of (bio)chemical and physical stimuli ( Nishimura et al, 2020 ). In basic angiogenesis research, they have been broadly used to study the impact of hemodynamic forces ( Akbari et al, 2019 ; Arpino et al, 2021 ; Zhao et al, 2021 ) as well as cell-cell ( Amemiya et al, 2021 ; Bai et al, 2021 ; Walji et al, 2021 ) and cell-matrix interactions ( Wang W. Y. et al, 2021 ; Liu et al, 2021 ) on the mechanisms of blood vessel development. Moreover, they represent attractive tools for the high-throughput screening of anti-angiogenic drugs ( Kim et al, 2015 ; Sobrino et al, 2016 ; Kim et al, 2021 ) ( Figure 3 ).…”

Section: In Vitro Assaysmentioning

confidence: 99%

Replacement in angiogenesis research: Studying mechanisms of blood vessel development by animal-free in vitro, in vivo and in silico approaches

Laschke

Gu²,

Menger³

2022

Front. Physiol.

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Angiogenesis, the development of new blood vessels from pre-existing ones, is an essential process determining numerous physiological and pathological conditions. Accordingly, there is a high demand for research approaches allowing the investigation of angiogenic mechanisms and the assessment of pro- and anti-angiogenic therapeutics. The present review provides a selective overview and critical discussion of such approaches, which, in line with the 3R principle, all share the common feature that they are not based on animal experiments. They include in vitro assays to study the viability, proliferation, migration, tube formation and sprouting activity of endothelial cells in two- and three-dimensional environments, the degradation of extracellular matrix compounds as well as the impact of hemodynamic forces on blood vessel formation. These assays can be complemented by in vivo analyses of microvascular network formation in the chorioallantoic membrane assay and early stages of zebrafish larvae. In addition, the combination of experimental data and physical laws enables the mathematical modeling of tissue-specific vascularization, blood flow patterns, interstitial fluid flow as well as oxygen, nutrient and drug distribution. All these animal-free approaches markedly contribute to an improved understanding of fundamental biological mechanisms underlying angiogenesis. Hence, they do not only represent essential tools in basic science but also in early stages of drug development. Moreover, their advancement bears the great potential to analyze angiogenesis in all its complexity and, thus, to make animal experiments superfluous in the future.

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“…The formation of new blood vessels from the existing vasculature, called angiogenesis, is regulated by different cells and processes ( Carmeliet, 2005 ; Eelen et al, 2020 ; Zhang et al, 2022 ). It is generally classified as sprouting angiogenesis (sprouting of endothelial cells from a mother vessel based on environmental cues) or intussusceptive angiogenesis (vessel splitting internally into two daughter vessels), with the former being better characterized and studied than the latter, and both essential for regeneration of microvasculature ( Arpino et al, 2021 ). Dysregulation in angiogenesis has been associated with the development and complication of different diseases, such as cancer, diabetic retinopathy, age-related macular degeneration, and cardiovascular diseases, including peripheral arterial disease (PAD) ( Zhang et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Endothelial cells signaling and patterning under hypoxia: a mechanistic integrative computational model including the Notch-Dll4 pathway

Oliveira,

Annex,

Popel

2024

Front. Physiol.

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Introduction: Several signaling pathways are activated during hypoxia to promote angiogenesis, leading to endothelial cell patterning, interaction, and downstream signaling. Understanding the mechanistic signaling differences between endothelial cells under normoxia and hypoxia and their response to different stimuli can guide therapies to modulate angiogenesis. We present a novel mechanistic model of interacting endothelial cells, including the main pathways involved in angiogenesis.Methods: We calibrate and fit the model parameters based on well-established modeling techniques that include structural and practical parameter identifiability, uncertainty quantification, and global sensitivity.Results: Our results indicate that the main pathways involved in patterning tip and stalk endothelial cells under hypoxia differ, and the time under hypoxia interferes with how different stimuli affect patterning. Additionally, our simulations indicate that Notch signaling might regulate vascular permeability and establish different Nitric Oxide release patterns for tip/stalk cells. Following simulations with various stimuli, our model suggests that factors such as time under hypoxia and oxygen availability must be considered for EC pattern control.Discussion: This project provides insights into the signaling and patterning of endothelial cells under various oxygen levels and stimulation by VEGFA and is our first integrative approach toward achieving EC control as a method for improving angiogenesis. Overall, our model provides a computational framework that can be built on to test angiogenesis-related therapies by modulation of different pathways, such as the Notch pathway.

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Low-flow intussusception and metastable VEGFR2 signaling launch angiogenesis in ischemic muscle

Abstract: The vasculature in ischemic muscle is rebuilt by the splitting of primordial vessels, led by VEGFR2-metastable endothelial cells.

Cited by 13 publications

References 66 publications

Angiogenesis precedes myogenesis during regeneration following biopsy injury in skeletal muscle

Angiogenesis precedes myogenesis during regeneration following biopsy injury in skeletal muscle

Replacement in angiogenesis research: Studying mechanisms of blood vessel development by animal-free in vitro, in vivo and in silico approaches

Endothelial cells signaling and patterning under hypoxia: a mechanistic integrative computational model including the Notch-Dll4 pathway

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