Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity.
Endothelial cell; Metastasis; Transient receptor potential vanilloid 4; Tumor angiogenesis; Vascular endothelial growth factor receptor 2
Transient receptor potential vanilloid 4 (TRPV4) is a ubiquitously expressed polymodally activated ion channel. TRPV4 has been implicated in tumor progression; however, the cell-specific role of TRPV4 in tumor growth, angiogenesis, and metastasis is unknown. Here, we generated endothelial-specific TRPV4 knockout (TRPV4(ECKO)) mice by crossing TRPV4(lox/lox) mice with Tie2-Cre mice. Tumor growth and metastasis were significantly increased in a syngeneic Lewis lung carcinoma tumor model of TRPV4(ECKO) mice compared to TRPV4(l)(ox/lox) mice. Multiphoton microscopy, dextran leakage, and immunohistochemical analysis revealed increased tumor angiogenesis and metastasis that were correlated with aberrant leaky vessels (increased width and reduced pericyte and VE-cadherin coverage). Mechanistically, increases in VEGFR2, p-ERK, and MMP-9 expression and DQ gelatinase activity were observed in the TRPV4(ECKO) mouse tumors. Our results demonstrated that endothelial TRPV4 is a critical modulator of vascular integrity and tumor angiogenesis and that deletion of TRPV4 promotes tumor angiogenesis, growth, and metastasis.
Kanugula AK; Adapala RK; Jamaiyar A; Lenkey N; Guarino BD; Liedtke W; Yin L; Paruchuri S; Thodeti CK
Angiogenesis
2021
2021-03-03
journalArticle
<a href="http://doi.org/10.1007/s10456-021-09775-9" target="_blank" rel="noreferrer noopener">10.1007/s10456-021-09775-9</a>
Endothelial Trpv4 contributes to pressure overload-induced pathological hypertrophy via modulation of coronary angiogenesis
Angiogenesis; Fibrosis; Ion channels; Cardiac hypertrophy;
Adapala RK; Kanugula AK; Ohanyan VA; Paruchuri SM; Chilian WM; Thodeti CK
Circulation Research
2020
2020-12-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/" target="_blank" rel="noreferrer noopener"></a>
Transient receptor potential vanilloid 4 channel deletion regulates pathological but not developmental retinal angiogenesis.
neovascularization; TRPV4; mechanotransduction; ECM stiffness; human retinal endothelial cells
Transient receptor potential vanilloid 4 (TRPV4) channels are mechanosensitive ion channels that regulate systemic endothelial cell (EC) functions such as vasodilation, permeability, and angiogenesis. TRPV4 is expressed in retinal ganglion cells, Müller glia, pigment epithelium, microvascular ECs, and modulates cell volume regulation, calcium homeostasis, and survival. TRPV4-mediated physiological or pathological retinal angiogenesis remains poorly understood. Here, we demonstrate that TRPV4 is expressed, functional, and mechanosensitive in retinal ECs. The genetic deletion of TRPV4 did not affect postnatal developmental angiogenesis but increased pathological neovascularization in response to oxygen-induced retinopathy (OIR). Retinal vessels from TRPV4 knockout mice subjected to OIR exhibited neovascular tufts that projected into the vitreous humor and displayed reduced pericyte coverage compared with wild-type mice. These results suggest that TRPV4 is a regulator of retinal angiogenesis, its deletion augments pathological retinal angiogenesis, and that TRPV4 could be a novel target for the development of therapies against neovascular ocular diseases.
Cappelli HC;Guarino BD;Kanugula AK;Adapala R K;Perera V;Smith MA;Paruchuri S;Thodeti CK
Journal of Cellular Physiology
2020
2020-10-20
journalArticle
<a href="http://doi.org/10.1002/jcp.30116" target="_blank" rel="noreferrer noopener">10.1002/jcp.30116</a>
Extracellular vesicles from tumor microenvironment transforms endothelial cell phenotype via downregulation of TRPV4 channels
Angiogenesis, the formation of new blood vessels from existing ones, is a normal physiological process. However, deregulation of angiogenesis can lead to pathological states such as cancer, that is characterized by hyper‐permeable and tortuous vessels. We have recently shown a significant decrease in functional expression of the mechanosensitive ion channel, transient potential receptor vanilloid 4 (TRPV4), in tumor endothelial cells (TEC). Further, pharmacological activation of TRPV4 induced normalization of tumor vasculature and improved cancer therapy. However, the molecular mechanisms by which TRPV4 is downregulated in TEC is not yet known. To determine this mechanism, we focused on extracellular vesicles (EVs) derived from tumor cells. We first collected conditioned media (TCM) from tumor cells with and without pre‐treatment of an exosome inhibitor, GW4869. We found that treatment of human normal endothelial cells (hNEC) with TCM transformed them into tumor‐endothelial like (hTEC) phenotype as revealed by expression of TEM8, VEGFR2 membrane translocation, and abnormal tube formation. However, TCM from exosome inhibitor‐treated cells, failed to induce endothelial transformation. Further, we found that EVs isolated from TCM induced hNEC transformation to hTEC. Mechanistically, we found that tumor derived EVs induced functional downregulation of TRPV4 in hNEC as assessed by calcium imaging. Taken together, our results suggest that tumor derived EVs transforms normal endothelial cells via downregulation of TRPV4 channels.
Guarino B;Adapala R;Kanugula A;Dougherty J;Paruchuri S;Mahmood K;Thodeti CK
Faseb Journal
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1096/fasebj.2020.34.s1.05946" target="_blank" rel="noreferrer noopener">10.1096/fasebj.2020.34.s1.05946</a>
The role of TRPV4 channels in ocular function and pathologies.
Glaucoma; TRPV4; Angiogenesis; Retina; Calcium channel; Cornea; Diabetic retinopathy; Lens; Osmolarity
Transient potential receptor vanilloid 4 (TRPV4) is an ion channel responsible for sensing osmotic and mechanical signals, which in turn regulates calcium signaling across cell membranes. TRPV4 is widely expressed throughout the body, and plays an important role in normal physiological function, as well as different pathologies, however, its role in the eye is not well known. In the eye, TRPV4 is expressed in various tissues, such as the retina, corneal epithelium, ciliary body, and the lens. In this review, we provide an overview on TRPV4 structure, activation, mutations, and summarize the current knowledge of TRPV4 function and signaling mechanisms in various locations throughout the eye, as well as its role in ocular diseases, such as glaucoma and diabetic retinopathy. Based on the available data, we highlight the therapeutic potential of TRPV4 as well as the shortcomings of current research. Finally, we provide future perspectives on the implications of targeting TRPV4 to treat various ocular pathologies. (Copyright © 2020 Elsevier Ltd. All rights reserved.)
Guarino BD;Paruchuri S;Thodeti CK
Experimental Eye Research
2020
2020-09-29
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.exer.2020.108257" target="_blank" rel="noreferrer noopener">10.1016/j.exer.2020.108257</a>
Transient receptor potential vanilloid channel regulates fibroblast differentiation and airway remodeling by modulating redox signals through NADPH oxidase 4.
ASTHMA; CAPSAICIN receptors; GROWTH factors; NICOTINAMIDE adenine dinucleotide phosphate; OXIDATION-reduction reaction; TRP channels
Asthma is characterized by pathological airway remodeling resulting from persistent myofibroblast activation. Although transforming growth factor beta 1 (TGFβ1), mechanical signals, and reactive oxygen species (ROS) are implicated in fibroblast differentiation, their integration is still elusive. We identified that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel mediates lung fibroblast (LF) differentiation and D. farinae-induced airway remodeling via a novel
Al-Azzam N; Teegala LR; Pokhrel S; Ghebreigziabher S; Chachkovskyy T; Thodeti S; Gavilanes I; Covington K; Thodeti CK; Paruchuri S
Scientific Reports
2020
2020-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1038/s41598-020-66617-2" target="_blank" rel="noreferrer noopener">10.1038/s41598-020-66617-2</a>