Transient Receptor Potential Vanilloid in the Brain Gliovascular Unit: Prospective Targets in Therapy

Abstract

The gliovascular unit (GVU) is composed of the brain microvascular endothelial cells forming blood–brain barrier and the neighboring surrounding “mural” cells (e.g., pericytes) and astrocytes. Modulation of the GVU/BBB features could be observed in a variety of vascular, immunologic, neuro-psychiatric diseases, and cancers, which can disrupt the brain homeostasis. Ca2+ dynamics have been regarded as a major factor in determining BBB/GVU properties, and previous studies have demonstrated the role of transient receptor potential vanilloid (TRPV) channels in modulating Ca2+ and BBB/GVU properties. The physiological role of thermosensitive TRPV channels in the BBB/GVU, as well as their possible therapeutic potential as targets in treating brain diseases via preserving the BBB are reviewed. TRPV2 and TRPV4 are the most abundant isoforms in the human BBB, and TRPV2 was evidenced to play a main role in regulating human BBB integrity. Interspecies differences in TRPV2 and TRPV4 BBB expression complicate further preclinical validation. More studies are still needed to better establish the physiopathological TRPV roles such as in astrocytes, vascular smooth muscle cells, and pericytes. The effect of the chronic TRPV modulation should also deserve further studies to evaluate their benefit and innocuity in vivo.

Transient Receptor Potential Channels in the Healthy and Diseased Blood–Brain Barrier

“…Third, TRPV4 activation induces the formation of actin stress fibers through PKC and phosphorylation of myosin light chain 2 and the consequence BBB disruption. The image has been published previously in Luo et al 100 Abbreviations: BBB, blood-brain barrier; BMECs, brain microvascular endothelial cells; TRPV1/4, transient receptor potential vanilloid 1/4; eNOS, endothelial nitric oxide synthase; ICH, intracerebral hemorrhage; RhoA, Ras homolog gene family member A; MLC2, myosin light chain 2; TJ, tight junction; AJ, adherens junction; PKC, phospholipase K; KCa, Ca 2+ -sensitive K + .…”

“…The TRPV subfamily comprises of six members located mostly in the plasma membrane, and they are divided in two subgroups: TRPV1–4 and TRPV5/6. 100,101 TRPV1–4 are also called “thermo-sensitive” TRPVs because they are activated by heat. 101 TRPV5/6 have different features compared with the other TRPV channels and they are not expressed in CNS 102 (Table 2).…”

“…First, the activation of TRPV4 induces an increase in Ca 2+ influx that stimulates Ca 2+ -sensitive K + channels 133 causing disruption of the BBB. 100,134 Second, the increased Ca 2+ levels via TRPV4 activation can also determine eNOS phosphorylation and the release of NO activation of high activating guanosine monophosphate (cGMP) levels. The high levels of cGMP lead to increased numbers of pinocytic vesicles containing caveolin-1 and caveolin-2 and alteration in BBB permeability by its disruption.…”

Receptor-Dependent and Independent Regulation of Voltage-Gated Ca2+ Channels and Ca2+-Permeable Channels by Endocannabinoids in the Brain

“…TRPV2 and TRPV4 are the two main isoforms present in the blood–brain barrier (BBB). TRPV2 plays a main role in the regulation of BBB permeability, thus its agonists may exert a protective effect via preserving or rescuing BBB integrity [ 134 ]. A growing body of evidence suggests that some channels can functionally interact with each other.…”