Regulation of Vessel Permeability by TRP Channels

Abstract

The vascular endothelium constitutes a semi-permeable barrier between blood and interstitial fluids. Since an augmented endothelial permeability is often associated to pathological states, understanding the molecular basis for its regulation is a crucial biomedical and clinical challenge. This review focuses on the processes controlling paracellular permeability that is the permeation of fluids between adjacent endothelial cells (ECs). Cytosolic calcium changes are often detected as early events preceding the alteration of the endothelial barrier (EB) function. For this reason, great interest has been devoted in the last decades to unveil the molecular mechanisms underlying calcium fluxes and their functional relationship with vessel permeability. Beyond the dicotomic classification between store-dependent and independent calcium entry at the plasma membrane level, the search for the molecular components of the related calcium-permeable channels revealed a difficult task for intrinsic and technical limitations. The contribution of redundant channel-forming proteins including members of TRP superfamily and Orai1, together with the very complex intracellular modulatory pathways, displays a huge variability among tissues and along the vascular tree. Moreover, calcium-independent events could significantly concur to the regulation of vascular permeability in an intricate and fascinating multifactorial framework.

Towards Novel Geneless Approaches for Therapeutic Angiogenesis

“…TRP channels provide an alternative pathway for extracellular Ca 2+ entry in both vascular endothelial cells ( Negri et al, 2020a ) and ECFCs ( Inoue and Xiong, 2009 ; Hofmann et al, 2014 ; Dragoni et al, 2015a ; Figure 1 ). Endothelial cells use TRP channels to sense the local microenvironment in which they reside, thereby adapting to subtle changes in the chemical composition of the extracellular milieu and/or in the mechanical forces acting on the vascular wall ( Genova et al, 2020 ; Negri et al, 2020a ). For instance, the endothelial TRPV1 is sensitive to an increase in local temperature above 43°C ( Negri et al, 2020b ) and/or in local hydrogen peroxide (H 2 O 2 ; DelloStritto et al, 2016 ), whereas TRPV4 is sensitive to physical stimuli, such as shear stress ( Schierling et al, 2011 ) and pulsatile stretch ( Thodeti et al, 2009 ), and to arachidonic acid (AA) production ( Fiorio Pla et al, 2008 ).…”

“…It has, therefore, been suggested that targeting TRP channels could represent an efficient strategy to boost ECFCs' regenerative potential (Moccia et al, 2015(Moccia et al, , 2018a. Indeed, TRP channels are physically coupled to specific Ca 2+ -dependent effectors which translate extracellular Ca 2+ entry through specific pathways into precise biological outputs which differentially affect endothelial cell fate (Smani et al, 2018;Genova et al, 2020;Negri et al, 2020a). ) and chemokines (like SDF-1) bind to Receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) respectively, thus activating specific PLC isoforms, which in turn leads to production of inositol 1,4,5-trisphosphate (InsP 3 ).…”

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

“…An increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) is the most versatile signaling pathway whereby either a subtle or gross change in extracellular microenvironment may instruct endothelial cells and circulating ECFCs to perform a specific task to maintain cardiovascular homeostasis [ 1 , 2 , 5 , 6 , 7 , 8 , 9 ]. Distinct spatiotemporal endothelial Ca 2+ signals tightly regulate different functions such as nitric oxide (NO) release [ 10 , 11 , 12 ] and endothelium-dependent hyperpolarization (EDH) [ 13 ], vascular permeability [ 14 , 15 ] and repair [ 16 , 17 ], platelet aggregation and blood coagulation [ 18 , 19 ], leukocyte/lymphocyte infiltration [ 20 , 21 , 22 , 23 ], neurovascular coupling [ 24 , 25 ], wound healing [ 16 , 17 ], angiogenesis [ 5 , 26 ], and vasculogenesis [ 27 ]. An aberrant, i.e., resulting either from intracellular Ca 2+ overload or by the dismantling of a specific oscillatory Ca 2+ pattern, or insufficient elevation in [Ca 2+ ] i may lead to endothelial dysfunction and therefore severely compromise cardiovascular homeostasis, as reported in atherosclerosis [ 28 ], hypertension [ 29 , 30 ], pulmonary artery hypertension (PAH) [ 31 ], type 2 diabetes [ 8 , 32 , 33 ], aging [ 34 ], inflammatory disorders [ 21 , 22 , 35 , 36 , 37 ], Alzheimer’s disease, and cerebrovascular dysfunction [ 34 , …”

TRP Channels as Cellular Targets of Particulate Matter

“…TRP channels can be activated and modulated by a wide variety of stimuli, including chemical agonists, temperature changes, mechanical stress, osmotic pressure and G-protein coupled receptor activation. They play important roles in multiple physiological processes, including nociception [ 12 , 13 , 14 ], thermosensation [ 15 , 16 ], chemosensation [ 17 ], regulation of the vascular tone and permeability [ 18 , 19 , 20 ], release of neuropeptides [ 21 ] and immune cell mediators [ 22 ], ciliary beating [ 23 , 24 , 25 ], mucus secretion [ 26 , 27 ], and barrier function in the airways and the skin [ 28 , 29 , 30 , 31 ].…”