TRPC and TRPV Channels’ Role in Vascular Remodeling and Disease

Abstract

Transient receptor potentials (TRPs) are non-selective cation channels that are widely expressed in vascular beds. They contribute to the Ca2+ influx evoked by a wide spectrum of chemical and physical stimuli, both in endothelial and vascular smooth muscle cells. Within the superfamily of TRP channels, different isoforms of TRPC (canonical) and TRPV (vanilloid) have emerged as important regulators of vascular tone and blood flow pressure. Additionally, several lines of evidence derived from animal models, and even from human subjects, highlighted the role of TRPC and TRPV in vascular remodeling and disease. Dysregulation in the function and/or expression of TRPC and TRPV isoforms likely regulates vascular smooth muscle cells switching from a contractile to a synthetic phenotype. This process contributes to the development and progression of vascular disorders, such as systemic and pulmonary arterial hypertension, atherosclerosis and restenosis. In this review, we provide an overview of the current knowledge on the implication of TRPC and TRPV in the physiological and pathological processes of some frequent vascular diseases.

A molecular complex of Ca v 1.2/CaMKK2/CaMK1a in caveolae is responsible for vascular remodeling via excitation–transcription coupling

“…These important changes are induced by activation of the Ca v 1.2/CaMKK2/CaMK1a axis. We suggest that high pressure can activate Ca v 1.2 in vascular myocytes directly via membrane stretch ( 57 ) or indirectly by depolarization due to the activation of mechanosensitive cation channels, such as TRP ( 58 ) and Piezo1 ( 59 ), in vascular myocytes. It is also interesting to note that recent papers provide evidence for the presence/expression of the same chemokines and adhesion molecules that we detected in this study in vascular myocytes in response to a broad range of stimuli, including mechanical stress ( 46 , 47 ), hypoxia ( 51 ), inflammation ( 60 ), and vascular injury ( 45 ).…”

mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target

“…Multiple cellular and molecular mechanisms are implicated in the development and progression of pulmonary vascular remodeling through enhanced PASMC proliferation and migration, such as the signaling cascades involving increases in intracellular free [Ca 2+ ], downregulation of K + channels and bone morphogenetic protein (BMP) receptors, upregulation of transforming growth factor-β (TGF-β) receptors, membrane receptors (e.g., Notch and CaSR) and Ca 2+ -permeable cation channels, and phosphorylation or activation of cytoplasmic kinases like AKT and mammalian target of rapamycin (mTOR) [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. However, the specific sequence of events involved in the enhanced PASMC proliferation in PH remains unclear.…”

Vascular Smooth Muscle Cells Mechanosensitive Regulators and Vascular Remodeling

“…In VSMCs, enhanced membrane stretch mediates elevated intracellular Ca 2+ and Na + via activation of TRPC1, TRPC3, and TRPC6 channels, leading to VSMC dysfunction [50]; TRPC6 is required to transduce stress-induced vasoconstriction in the middle cerebral artery (MCA) of mice and is localized in cerebral VSMCs, and the pressure-induced vasoconstriction disappears in the MCA of TRPC6-knockout mice [51, 52]. TRPC6 regulates the phenotype of VSMCs via a cell membrane potential with PTEN-dependent coupling [53].…”

“…Piezo1 gene deletion leads to a significant reduction in the arterial diameter, wall thickness, and cross-sectional area [43]. In an SHR disease model, multiple isoforms of TRP channels are activated and activated TRP mediates elevated intracellular Ca 2+ and Na + [50]. In PAH, TRPM7 is downregulated to activate the MEK/ERK pathway and intracellular Mg 2+ levels are reduced [59]; in addition, mechanical stretch potentiating the Ang II type 1/EGFR/ERK-dependent signaling pathway directly regulates VSMC proliferation induced in SHR [133].…”