Endothelial TRPV4 channels in lung edema and injury

Sonkusare, Swapnil K.; Laubach, Victor E.

doi:10.1016/bs.ctm.2022.07.001

Cited by 15 publications

(15 citation statements)

References 85 publications

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“…Although TRPV4 was demonstrated to regulate EC function, most of the work was focused on its role in hypertension and barrier function. 17,18 We have previously demonstrated that TRPV4 channels are mechanically activated by ECM stiffness and cyclic stretch in ECs and regulate tumor angiogenesis. [5][6][7][8][9][19][20][21][22][23] In the present study, by using an endothelial-specific TRPV4KO mice, we demonstrated that deletion of TRPV4, specifically in ECs (but not in fibroblasts or cardiomyocytes), preserved cardiac function and reduced cardiac hypertrophy and cardiac fibrosis via increased coronary angiogenesis (Figure S9).…”

Section: Discussionmentioning

confidence: 99%

Deletion of Endothelial TRPV4 Protects Heart From Pressure Overload–Induced Hypertrophy

Adapala,

Katari,

Kanugula

et al. 2023

Hypertension

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BACKGROUND: Left ventricular hypertrophy is a bipolar response, starting as an adaptive response to the hemodynamic challenge, but over time develops maladaptive pathology partly due to microvascular rarefaction and impaired coronary angiogenesis. Despite the profound influence on cardiac function, the mechanotransduction mechanisms that regulate coronary angiogenesis, leading to heart failure, are not well known. METHODS: We subjected endothelial-specific knockout mice of mechanically activated ion channel, TRPV4 (transient receptor potential cation channel subfamily V member 4; TRPV4 ECKO ) to pressure overload via transverse aortic constriction and examined cardiac function, cardiomyocyte hypertrophy, cardiac fibrosis, and apoptosis. Further, we measured microvascular density and underlying TRPV4 mechanotransduction mechanisms using human microvascular endothelial cells, extracellular matrix gels of varying stiffness, unbiased RNA sequencing, small interfering RNA, Western blot, quantitative-PCR, and confocal immunofluorescence techniques. RESULTS: We demonstrate that endothelial-specific deletion of TRPV4 preserved cardiac function, cardiomyocyte structure, and reduced cardiac fibrosis compared with TRPV4 lox/lox mice, 28 days post–transverse aortic constriction. Interestingly, comprehensive RNA sequencing analysis revealed an upregulation of proangiogenic factors (VEGFα [vascular endothelial growth factor α], NOS3 [nitric oxide synthase 3], and FGF2 [fibroblast growth factor 2]) with concomitant increase in microvascular density in TRPV4 ECKO hearts after transverse aortic constriction compared with TRPV4 lox/lox . Further, an increased expression of VEGFR2 (vascular endothelial growth factor receptor 2) and activation of the YAP (yes-associated protein) pathway were observed in TRPV4 ECKO hearts. Mechanistically, we found that downregulation of TRPV4 in endothelial cells induced matrix stiffness–dependent activation of YAP and VEGFR2 via the Rho/Rho kinase/large tumor suppressor kinase pathway. CONCLUSIONS: Our results suggest that endothelial TRPV4 acts as a mechanical break for coronary angiogenesis, and uncoupling endothelial TRPV4 mechanotransduction attenuates pathological cardiac hypertrophy by enhancing coronary angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Deletion of Endothelial TRPV4 Protects Heart From Pressure Overload–Induced Hypertrophy

Adapala,

Katari,

Kanugula

et al. 2023

Hypertension

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“…Several previously published studies provided evidence that endothelial TRPV4 channels are involved in various models of acute lung injury ( 12 , 13 , 15 ). We showed that endothelial TRPV4 channels play a critical role in lung IRI ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

“…Transient receptor potential vanilloid 4 (TRPV4) channels, which constitute a major Ca 2+ entry pathway in pulmonary endothelium ( 8 , 10 , 11 ), have emerged as central players in the pathogenesis of different forms of lung injury ( 12 – 15 ). We provided evidence that endothelial TRPV4-knockout ( Trpv4 ECKO ) mice are protected against increased vascular permeability, lung inflammation, and edema after lung IR ( 16 ), suggesting that endothelial TRPV4 channels are critical mediators of lung IRI.…”

Section: Introductionmentioning

confidence: 99%

Purinergic P2Y2 receptor–induced activation of endothelial TRPV4 channels mediates lung ischemia-reperfusion injury

Kuppusamy,

Ta,

Davenport

et al. 2023

Sci. Signal.

Self Cite

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Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung transplantation. Here, we investigated the cellular mechanisms underlying lung IR–induced activation of endothelial TRPV4 channels, which play a central role in lung edema and dysfunction after IR. In a left lung hilar-ligation model of IRI in mice, we found that lung IRI increased the efflux of ATP through pannexin 1 (Panx1) channels at the endothelial cell (EC) membrane. Elevated extracellular ATP activated Ca 2+ influx through endothelial TRPV4 channels downstream of purinergic P2Y2 receptor (P2Y2R) signaling. P2Y2R-dependent activation of TRPV4 channels was also observed in human and mouse pulmonary microvascular endothelium in ex vivo and in vitro models of IR. Endothelium-specific deletion of P2Y2R, TRPV4, or Panx1 in mice substantially prevented lung IRI–induced activation of endothelial TRPV4 channels and lung edema, inflammation, and dysfunction. These results identify endothelial P2Y2R as a mediator of the pathological sequelae of IRI in the lung and show that disruption of the endothelial Panx1-P2Y2R-TRPV4 signaling pathway could be a promising therapeutic strategy for preventing lung IRI after transplantation.

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Section: Introductionmentioning

confidence: 99%

“…Removal of the distal N-terminus results in loss of sensitivity to swelling whereas its replacement with a truncated domain of the cognate TRPV1 converted TRPV4 into a shrinking sensor (Toft-Bertelsen, Yarishkin et al 2019). The channel has been implicated in osmosignaling in neurons, glia, epithelial cells, endothelial cells, heterologously expressing HEK293 cells and oocytes (Liedtke and Friedman 2003, Ryskamp, Jo et al 2014, Phuong, Redmon et al 2017, Toft-Bertelsen, Yarishkin et al 2019, Lapajne, Lakk et al 2020, Sonkusare and Laubach 2022) but not keratinocytes (Ritzmann, Jahn et al 2023). TRPV4 modulates systemic osmoregulation (Liedtke and Friedman 2003), water diffusion and edema formation in the retina, lung and brain (Hoshi, Okabe et al 2018, Orduna Rios, Noguez Imm et al 2019, Sonkusare and Laubach 2022) but its role in volume regulation has been under debate, with studies implicating it in the promotion of swelling (Jo, Ryskamp et al 2015, Barile, Mola et al 2023) and regulatory volume decrease (RVD) (Becker, Blase et al 2005, Hoffmann, Lambert et al 2009, Jo, Ryskamp et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Osmosensing in trabecular meshwork cells

Baumann,

Yarishkin,

Lakk

et al. 2024

Preprint

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Aqueous humor drainage from the anterior eye constitutes a key determinant of intraocular pressure (IOP) under homeostatic and pathological conditions. Swelling of the trabecular meshwork (TM) increases its flow resistance but the mechanisms that sense and transduce osmotic gradients remain poorly understood. We used optical molecular analyses, optical imaging and electrophysiology to investigate TM osmotransduction and its role in calcium and chloride homeostasis. Anisosmotic conditions elicited proportional changes in TM cell volume. Swelling, but not shrinking, evoked increases in intracellular calcium concentration [Ca2+]TM. Hypotonicity-evoked calcium signals were sensitive to HC067047, a selective blocker of TRPV4 channels, whereas the agonist GSK1016790A promoted swelling under isotonic conditions. TRPV4 inhibition partially suppressed hypotonicity-induced volume increases and reduced the magnitude of the swelling-induced membrane current, with a substantial fraction of the swelling-evoked current abrogated by Cl-channel antagonists DIDS and niflumic acid. The volume-sensing transcriptome of primary human TM cells showed expression of TRPV4, TRPM4, AQP1, and TMEMC3B genes. Cl-channel expression was dominated by ANO6 transcripts, auxiliary levels of ANO3, ANO7 and ANO10 and modest expression of LTTRC genes that encode volume-activated anion channels. Thus, TRPV4-mediated cation influx works with Cl-efflux to sense and respond to osmotic stress, potentially contributing to pathological swelling, calcium overload and intracellular signaling that could exacerbate functional disturbances in inflammatory disease and glaucoma.

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Endothelial TRPV4 channels in lung edema and injury

Cited by 15 publications

References 85 publications

Deletion of Endothelial TRPV4 Protects Heart From Pressure Overload–Induced Hypertrophy

Deletion of Endothelial TRPV4 Protects Heart From Pressure Overload–Induced Hypertrophy

Purinergic P2Y2 receptor–induced activation of endothelial TRPV4 channels mediates lung ischemia-reperfusion injury

Osmosensing in trabecular meshwork cells

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