Vascular mechanotransduction

Physiological Reviews, Год журнала: 2023, Номер 103(2), С. 1247 - 1421

Опубликована: Янв. 5, 2023

This review aims to survey the current state of mechanotransduction in vascular smooth muscle cells (VSMCs) and endothelial (ECs), including their sensing mechanical stimuli transduction signals that result acute functional modulation longer-term transcriptomic epigenetic regulation blood vessels. The mechanosensors discussed include ion channels, plasma membrane-associated structures receptors, junction proteins. mechanosignaling pathways presented cytoskeleton, integrins, extracellular matrix, intracellular signaling molecules. These are followed by discussions on transcriptome epigenetics, relevance health disease, interactions between VSMCs ECs. Throughout this review, we offer suggestions for specific topics require further understanding. In closing section conclusions perspectives, summarize what is known point out need treat vasculature as a system, not only ECs but also matrix other types such resident macrophages pericytes, so can fully understand physiology pathophysiology vessel whole, thus enhancing comprehension, diagnosis, treatment, prevention diseases.

Язык: Английский

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Endothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm formation

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Март 21, 2022

Pannexin-1 (Panx1) channels have been shown to regulate leukocyte trafficking and tissue inflammation but the mechanism of Panx1 in chronic vascular diseases like abdominal aortic aneurysms (AAA) is unknown. Here we demonstrate that on endothelial cells, not smooth muscle orchestrate a cascade signaling events mediate remodeling. Mechanistically, cells acts as conduit for ATP release stimulates macrophage activation via P2X7 receptors mitochondrial DNA increase IL-1β HMGB1 secretion. Secondly, regulates cell-dependent intracellular Ca2+ remodeling P2Y2 receptors. blockade using probenecid markedly inhibits transmigration, mitigate AAA formation. expression upregulated human AAAs retrospective clinical data demonstrated reduced mortality aneurysm patients treated with inhibitors. Collectively, these identify contributory

Язык: Английский

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Novel Smooth Muscle Ca ²⁺ -Signaling Nanodomains in Blood Pressure Regulation

Circulation, Год журнала: 2022, Номер 146(7), С. 548 - 564

Опубликована: Авг. 15, 2022

Ca2+ signals in smooth muscle cells (SMCs) contribute to vascular resistance and control blood pressure. Increased hypertension has been attributed impaired SMC signaling mechanisms. In this regard, transient receptor potential vanilloid 4 (TRPV4SMC) ion channels are a crucial entry pathway SMCs. However, their role pressure regulation not identified.We used SMC-specific TRPV4-/- (TRPV4SMC-/-) mice assess the of TRPV4SMC regulation. We determined contribution constrictor effect α1 adrenergic (α1AR) stimulation elevated intraluminal pressure: 2 main physiologic stimuli that constrict resistance-sized arteries. The spatially separated channel subpopulations was evaluated angiotensin II-infused patients with hypertension.We provide first evidence activity elevates resting normal mice. α1AR activated through PKCα (protein kinase Cα) signaling, which contributed significantly vasoconstriction elevation. Intraluminal pressure-induced opposed activation Ca2+-sensitive K+ (BK) channels, indicating functionally opposite pools channels. Superresolution imaging SMCs revealed α1AR:TRPV4 TRPV4:BK nanodomains These data suggest α1AR-TRPV4SMC pressure-TRPV4SMC-BK have effects on pressure, dominating under conditions. Furthermore, mouse model hypertension, α1AR-PKCα-TRPV4 upregulated, whereas dilator pressure-TRPV4-BK disrupted, thereby increasing elevating pressure.Our identify novel Ca2+-signaling regulate demonstrate impairment hypertension.

Язык: Английский

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Flow-Induced Shear Stress Primes NLRP3 Inflammasome Activation in Macrophages via Piezo1

ACS Applied Materials & Interfaces, Год журнала: 2024, Номер 16(4), С. 4505 - 4518

Опубликована: Янв. 19, 2024

The NLRP3 inflammasome is a crucial component of the innate immune system, playing pivotal role in initiating and regulating body's inflammatory response to various pathogens cellular damage. Environmental stimuli, such as temperature, pH level, nutrient availability, can influence behavior functions cells, including cell activity, proliferation, cytokine production. However, there limited understanding regarding how mechanical forces, like shear stress, govern intrinsic reaction, particularly activation inflammasome, stress impacts through its capacity induce alterations gene expression secretion. Here, we investigated act priming signal by exposing immortalized bone marrow-derived macrophages (iBMDMs) numerous physiologically relevant magnitudes before chemically inducing activation. We demonstrated that large was able prime iBMDMs more effectively for compared lower magnitudes, quantified percentage cells where ASC-CFP specks formed IL-1β secretion, hallmarks Testing this caspase-1 knockout showed primarily primed due exposure. Quantitative polymerase chain reaction (qPCR) small-molecule inhibitor study mechanistically determined regulates upregulating Piezo1, IKKβ, NLRP3. These findings offer insights into mechanistic relationship among physiological stresses, activation, their impact on progression diseases interconnected pathogenesis.

Язык: Английский

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Mechanosensitive membrane domains regulate calcium entry in arterial endothelial cells to protect against inflammation

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(13)

Опубликована: Май 21, 2024

Endothelial cells (ECs) in the descending aorta are exposed to high laminar shear stress, and this supports an anti-inflammatory phenotype. High stress also induces flow-aligned cell elongation front-rear polarity, but whether these required for phenotype is unclear. Here, we showed that Caveolin-1-rich microdomains polarize downstream end of ECs continuous flow. These were characterized by membrane rigidity, filamentous actin (F-actin), raft-associated lipids. Transient receptor potential vanilloid-type 4 (TRPV4) ion channels ubiquitously expressed on plasma mediated localized Ca2+ entry only at where they physically interacted with clustered Caveolin-1. focal bursts activated endothelial nitric oxide synthase (eNOS) within confines domains. Importantly, found signaling domains both body sustained Finally, TRPV4 was necessary sufficient suppress inflammatory gene expression, exogenous activation ameliorated response stimuli vitro vivo. Our work revealed a polarized mechanosensitive hub arterial dampens expression promotes resilience.

Язык: Английский

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Vascular Smooth Muscle TRPV4 (Transient Receptor Potential Vanilloid Family Member 4) Channels Regulate Vasoconstriction and Blood Pressure in Obesity

Hypertension, Год журнала: 2023, Номер 80(4), С. 757 - 770

Опубликована: Фев. 16, 2023

Vascular endothelium and smooth muscle work together to keep the balance of vasomotor tone jointly maintain vascular homeostasis. Ca2+-permeable ion channel TRPV4 (transient receptor potential vanilloid family member 4) in endothelial cells regulates endothelium-dependent vasodilation contraction various states. However, how cell (TRPV4SMC) contributes function blood pressure regulation physiological pathologically obese condition has not been fully studied.We generated TRPV4-deficient mice developed diet-induced model analyzed role TRPV4SMC intracellular Ca2+ ([Ca2+]i) vasoconstriction. Vasomotor changes mouse mesenteric artery were measured by wire, myography. [Ca2+]i fluo-4 staining. Blood was recorded telemetric device.Vascular played different roles regulating than due their features regulation. Loss attenuated U46619- phenylephrine-induced contraction, suggesting its involvement contractility. Mesenteric arteries from showed SMC hyperplasia, an increased level TRPV4SMC. did influence development obesity but protected obesity-induced vasoconstriction hypertension. In deficient TRPV4, SMCs F-actin polymerization RhoA dephosphorylation under contractile stimuli. Moreover, SMC-dependent inhibited human resistance with inhibitor application.Our data identify as a regulator both states mice. ontogeny hypertension induced over-expression artery.

Язык: Английский

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Investigating the Role of TRPV4 and GPR35 Interaction in Endothelial Dysfunction in Aging Mice

Aging Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

Endothelial dysfunction, characterized by a decline in endothelial physiological functions, is significant aspect of cardiovascular aging, contributing notably to arterial stiffness, atherosclerosis, and hypertension. Transient receptor potential channel V4 (TRPV4), key member Ca

Язык: Английский

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Cracking the Endothelial Calcium (Ca2+) Code: A Matter of Timing and Spacing

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(23), С. 16765 - 16765

Опубликована: Ноя. 26, 2023

A monolayer of endothelial cells lines the innermost surface all blood vessels, thereby coming into close contact with every region body and perceiving signals deriving from both bloodstream parenchymal tissues. An increase in intracellular Ca2+ concentration ([Ca2+]i) is main mechanism whereby vascular integrate information conveyed by local circulating cues. Herein, we describe dynamics spatial distribution to understand how an array spatially restricted (at subcellular cellular levels) exploited intima fulfill this complex task. We then illustrate affect most appropriate function are integrated transmit more distant sites maintain cardiovascular homeostasis. Vasorelaxation sprouting angiogenesis were selected as example functions that finely tuned variable spatio-temporal profile signals. further highlighted distinct signatures regulate different phases vasculogenesis, i.e., proliferation migration, precursors.

Язык: Английский

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FHL5 Controls Vascular Disease–Associated Gene Programs in Smooth Muscle Cells

Circulation Research, Год журнала: 2023, Номер 132(9), С. 1144 - 1161

Опубликована: Апрель 5, 2023

Background: Genome-wide association studies have identified hundreds of loci associated with common vascular diseases, such as coronary artery disease, myocardial infarction, and hypertension. However, the lack mechanistic insights for many GWAS limits their translation into clinic. Among these unknown functions is UFL1 –four-and-a-half LIM (LIN-11, Isl-1, MEC-3) domain 5 ( FHL5 ; chr6q16.1), which reached genome-wide significance in a recent disease/ infarction meta-analysis. UFL1-FHL5 also several consistent widespread pleiotropy observed loci. Methods: We apply multimodal approach leveraging statistical fine-mapping, epigenomic profiling, ex vivo analysis human tissues to implicate top candidate causal gene. unravel molecular mechanisms cross-phenotype genetic associations through vitro functional analyses profiling experiments smooth muscle cells. Results: prioritized gene at locus expression quantitative trait colocalization methods. was enriched cells pericyte population coexpression network supporting role regulating cell contraction. Unexpectedly, under procalcifying conditions, overexpression promoted calcification dysregulated processes related extracellular matrix organization calcium handling. Lastly, by mapping binding sites inferring target function using tissue regulatory analyses, we highlight interactions between downstream disease/myocardial loci, FOXL1 FN1 that roles remodeling. Conclusions: Taken together, provide pleiotropic UFL1-FHL5. show mediates disease risk transcriptional regulation remodeling programs. These transacting may explain portion heritable complex diseases.

Язык: Английский

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Vasodilators activate the anion channel TMEM16A in endothelial cells to reduce blood pressure

Science Signaling, Год журнала: 2023, Номер 16(811)

Опубликована: Ноя. 14, 2023

Systemic blood pressure is acutely controlled by total peripheral resistance as determined the diameter of small arteries and arterioles, contractility which regulated endothelial cells lining lumen vessels. We investigated physiological functions chloride (Cl − ) channel TMEM16A in cells. channels generated calcium (Ca 2+ )–activated Cl currents from control ( fl/fl mice that were absent those with tamoxifen-inducible, cell–specific knockout ecKO). activated muscarinic receptor agonist acetylcholine an Ca TRPV4, localized nanoscale proximity assessed single-molecule localization imaging Acetylcholine stimulated activating influx through surface TRPV4 without altering properties clusters or their colocalization. In pressurized arteries, activation induced acetylcholine; stimulation; intraluminal ATP, another vasodilator, produced hyperpolarization dilation. Furthermore, deficiency resulted increased systemic conscious mice. These data indicate vasodilators stimulate channels, leading to -dependent nearby produce arterial hyperpolarization, vasodilation, reduced pressure. Thus, anion regulates

Язык: Английский

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