Microvessel Density: Integrating Sex-Based Differences and Elevated Cardiovascular Risks in Metabolic Syndrome

Wong, Arthur; Chen, Shuqing; Halvorson, Brayden D.; Frisbee, Jefferson C.

doi:10.1159/000518787

Cited by 7 publications

(9 citation statements)

References 109 publications

(122 reference statements)

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“…In the results of the present study, the VHI clearly indicates that the decline in integrated microvascular structure and function with the progression of metabolic disease in male OZR was significant, multi-factorial, and was consistent over multiple years, multiple cohorts of animals, and-perhaps most importantly-over multiple groups of investigators collecting the data/results. While the contributing mechanisms for the shift in vascular reactivity (Benincasa et al, 2022;Zhang, 2022), vascular wall mechanics (Lacolley et al, 2020;Laurent et al, 2022) and microvessel density (Paavonsalo et al, 2020;Wong et al, 2022) have been extensively presented and discussed elsewhere, this speaks directly to the discriminant validity of the VHI metric and is also evident in Figures 2C, 3B,C, 4B.…”

Section: Discussionmentioning

confidence: 91%

“…From a purely conceptual perspective, this adds insight and information from the “vascular network” level of resolution and speaks directly to the importance of vascularity/capillarity within the tissue under the spectrum of experimental conditions. The existing literature is replete with examples of how MVD, determined using multiple methodologies, changes with elevated disease risk and following therapeutic interventions ( Liang et al, 2019 ; Paavonsalo et al, 2020 ; Wong et al, 2022 ). The ability to include data and insight into both the pro-angiogenic and rarefactory stimuli under an array of experimental conditions is critical for assessing the overall health and functional outcomes of the tissue.…”

Section: Discussionmentioning

confidence: 99%

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A novel vascular health index: Using data analytics and population health to facilitate mechanistic modeling of microvascular status

Menon

Halvorson²,

Alimorad³

et al. 2022

Front. Physiol.

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The study of vascular function across conditions has been an intensive area of investigation for many years. While these efforts have revealed many factors contributing to vascular health, challenges remain for integrating results across research groups, animal models, and experimental conditions to understand integrated vascular function. As such, the insights attained in clinical/population research from linking datasets, have not been fully realized in the basic sciences, thus frustrating advanced analytics and complex modeling. To achieve comparable advances, we must address the conceptual challenge of defining/measuring integrated vascular function and the technical challenge of combining data across conditions, models, and groups. Here, we describe an approach to establish and validate a composite metric of vascular function by comparing parameters of vascular function in metabolic disease (the obese Zucker rat) to the same parameters in age-matched, “healthy” conditions, resulting in a common outcome measure which we term the vascular health index (VHI). VHI allows for the integration of datasets, thus expanding sample size and permitting advanced modeling to gain insight into the development of peripheral and cerebral vascular dysfunction. Markers of vascular reactivity, vascular wall mechanics, and microvascular network density are integrated in the VHI. We provide a detailed presentation of the development of the VHI and provide multiple measures to assess face, content, criterion, and discriminant validity of the metric. Our results demonstrate how the VHI captures multiple indices of dysfunction in the skeletal muscle and cerebral vasculature with metabolic disease and provide context for an integrated understanding of vascular health under challenged conditions.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

A novel vascular health index: Using data analytics and population health to facilitate mechanistic modeling of microvascular status

Menon

Halvorson²,

Alimorad³

et al. 2022

Front. Physiol.

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“…For example, estrogen has been implied in coronary microvascular dysfunction and fibrosis. 42,43 to avoid the impact of female hormone cycles on microvessels, we only used male rats in this study. Therefore, the study has certain limitations, and the in vivo efficacy of the joint regulation strategy warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…The paired bone grafts were implanted into rats subcutaneously for 2 weeks before harvest. To avoid the potential effect of the hormone cycle of female rats on the microvessels, 42,43 we only used male rats of 8 to 10 weeks in this study. The tissues between the paired bone grafts were fixed in 4% paraformaldehyde and embedded in optimal cutting temperature for cryosection.…”

Section: Methodsmentioning

confidence: 99%

“…The isolation of primary microvessels from rat subcutaneous soft connective tissue was performed as described previously. 41 To avoid potential effect of the hormone cycle of female rats on the microvessels, 42,43 we only used the male Sprague Dawley rats of 8 to 10 weeks in this study. Briefly, the tissue pieces were digested in the enzymatic solution containing 2 mg/mL collagenase type 1 (Worthington; catalog number LS004196), 5 mg/mL BSA (Sigma; catalog number A1933), and 5 µM Y27632 (Selleck; catalog number S1049) in DMEM (Dulbecco's modified eagle medium) at 37 °C by cyclic digestion.…”

Section: Primary Microvessel Culturementioning

confidence: 99%

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Extracellular Matrix Stiffness Regulates Microvascular Stability by Controlling Endothelial Paracrine Signaling to Determine Pericyte Fate

Yu,

Leng,

Song

et al. 2023

ATVB

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BACKGROUND: The differentiation of pericytes into myofibroblasts causes microvascular degeneration, ECM (extracellular matrix) accumulation, and tissue stiffening, characteristics of fibrotic diseases. It is unclear how pericyte-myofibroblast differentiation is regulated in the microvascular environment. Our previous study established a novel 2-dimensional platform for coculturing microvascular endothelial cells (ECs) and pericytes derived from the same tissue. This study investigated how ECM stiffness regulated microvascular ECs, pericytes, and their interactions. METHODS: Primary microvessels were cultured in the tubular microvascular growth medium on 2-dimensional stiff substrates. Stiff ECM was prepared by incubating ECM solution in regular culture dishes for 1 hour followed by PBS wash. Soft ECM with Young modulus of ≈6 kPa was used unless otherwise noted. Bone grafts were prepared from the rat skull. Immunostaining, RNA sequencing, qRT-PCR, Western blotting, and knockdown experiments were performed on the cells. RESULTS: Primary microvascular pericytes differentiated into myofibroblasts (NG2 + αSMA + ) on stiff ECM, even with the TGFβ (transforming growth factor beta) signaling inhibitor A83-01. Soft ECM and A83-01 cooperatively maintained microvascular stability while inhibiting pericyte-myofibroblast differentiation (NG2 + αSMA −/low ). We thus defined 2 pericyte subpopulations: primary (NG2 + αSMA −/low ) and activated (NG2 + αSMA + ) pericytes. Soft ECM promoted microvascular regeneration and inhibited fibrosis in bone graft transplantation in vivo. As integrins are the major mechanosensor, we performed qRT-PCR screening of integrin family members and found Itgb1 (integrin β1) was the major subunit downregulated by soft ECM and A83-01 treatment. Knocking down Itgb1 suppressed myofibroblast differentiation on stiff ECM. Interestingly, ITGB1 phosphorylation (Y783) was mainly located on microvascular ECs on stiff ECM, which promoted EC secretion of paracrine factors, including CTGF (connective tissue growth factor), to induce pericyte-myofibroblast differentiation. CTGF knockdown or monoclonal antibody treatment partially reduced myofibroblast differentiation, implying the participation of multiple pathways in fibrosis formation. CONCLUSIONS: ECM stiffness and TGFβ signaling cooperatively regulate microvascular stability and pericyte-myofibroblast differentiation. Stiff ECM promotes EC ITGB1 phosphorylation (Y783) and CTGF secretion, which induces pericyte-myofibroblast differentiation.

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Capillary communication: the role of capillaries in sensing the tissue environment, coordinating the microvascular, and controlling blood flow

Murrant

Fletcher

2022

American Journal of Physiology-Heart and Circulatory Physiology

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Historically, capillaries have been viewed as the microvascular site for flux of nutrients to cells and removal of waste products. Capillaries are the most numerous blood vessel segment within the tissue, whose vascular wall consists of only a single layer of endothelial cells, and are situated within microns of each cell of the tissue, all of which optimizes capillaries for the exchange of nutrients between the blood compartment and the interstitial space of tissues. There is, however, a growing body of evidence to support that capillaries play an important role in sensing the tissue environment, coordinating microvascular network responses and controlling blood flow. Much of our growing understanding of capillaries stems from work in skeletal muscle and more recent work in the brain, where capillaries can be stimulated by products released from cells of the tissue during increased activity, and are able to communicate with upstream and downstream vascular segments, enabling capillaries to sense the activity levels of the tissue and send signals to the microvascular network to coordinate the blood flow response. This review will focus on the emerging role that capillaries play in communication between cells of the tissue and the vascular network required to direct blood flow to active cells in skeletal muscle and the brain. We will also highlight the emerging central role that disruptions in capillary communication may play in blood flow dysregulation, pathophysiology and disease.

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Microvessel Density: Integrating Sex-Based Differences and Elevated Cardiovascular Risks in Metabolic Syndrome

Cited by 7 publications

References 109 publications

A novel vascular health index: Using data analytics and population health to facilitate mechanistic modeling of microvascular status

A novel vascular health index: Using data analytics and population health to facilitate mechanistic modeling of microvascular status

Extracellular Matrix Stiffness Regulates Microvascular Stability by Controlling Endothelial Paracrine Signaling to Determine Pericyte Fate

Capillary communication: the role of capillaries in sensing the tissue environment, coordinating the microvascular, and controlling blood flow

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