Transient receptor potential vanilloid 4 channels are important regulators of parenchymal arteriole dilation and cognitive function

Abstract

Objective Hypertension‐associated PA dysfunction reduces cerebral perfusion and impairs cognition. This is associated with impaired TRPV4‐mediated PA dilation; therefore, we tested the hypothesis that TRPV4 channels are important regulators of cerebral perfusion, PA structure and dilation, and cognition. Methods Ten‐ to twelve‐month‐old male TRPV4 knockout (WKY‐Trpv4em4Mcwi) and age‐matched control WKY rats were studied. Cerebral perfusion was measured by MRI with arterial spin labeling. PA structure and function were assessed using pressure myography and cognitive function using the novel object recognition test. Results Cerebral perfusion was reduced in the WKY‐Trpv4em4Mcwi rats. This was not a result of PA remodeling because TRPV4 deletion did not change PA structure. TRPV4 deletion did not change PA myogenic tone development, but PAs from the WKY‐Trpv4em4Mcwi rats had severely blunted endothelium‐dependent dilation. The WKY‐Trpv4em4Mcwi rats had impaired cognitive function and exhibited depressive‐like behavior. The WKY‐Trpv4em4Mcwi rats also had increased microglia activation, and increased mRNA expression of GFAP and tumor necrosis factor alpha suggesting increased inflammation. Conclusion Our data indicate that TRPV4 channels play a critical role in cerebral perfusion, PA dilation, cognition, and inflammation. Impaired TRPV4 function in diseases such as hypertension may increase the risk of the development of vascular dementia.

Vasculo-Neuronal Coupling and Neurovascular Coupling at the Neurovascular Unit: Impact of Hypertension

“…The authors then evaluated the role of TRPV4 channels in vessel dysfunction using a TRPV4-knockout rat model [WKY-Trpv4(em4Mcwi)], reporting reduced cerebral perfusion with no changes in parenchymal arteriole structure or myogenic tone. However, these rats did show impaired endothelium-dependent dilation and cognitive function in association with gliosis (Diaz-Otero et al, 2019). It has further been shown that relaxation of VSMCs is diminished in mesenteric arteries of SHR and SHRSP models; this effect was attributed to a decrease in the generation of the endothelium-dependent hyperpolarizing factor, a process that likely depends on TRPV4 and SK channel signaling (Seki et al, 2017).…”

Advancement in research on the role of the transient receptor potential vanilloid channel in cerebral ischemic injury (Review)

“…TRPV4 in inflammation and apoptosis. TRPV4 is a non-selective, calcium-permeable cation channel that serves a critical role in cerebral perfusion and inflammation (81). It has been reported that TRPV4 is activated in choroid plexus epithelia and cerebral ischemia by cytokines and inflammatory mediators, such as TNF-α, IL-1β and TGF-β1 (82,83).…”

Glial Interfaces: Advanced Materials and Devices to Uncover the Role of Astroglial Cells in Brain Function and Dysfunction

“…[59,60] Recently, the relevance of TRPV4 in cerebrovascular function was highlighted when researchers found an impairment in the cognitive function of mice lacking the channel protein. [86,87] Several lines of in vivo evidence indicated that astrocytes can modulate or enhance neuronal oscillations and synchronization, which are both important mechanisms for memory formation, learning, and sensory perception. Activation of astrocytes can also coordinate the activity of neuronal networks and their transition from desynchronized states to synchronized, oscillatory states.…”

“…[113] Thus, it would be interesting to explore if P3HT:PCBM blend photostimulation might perturb calcium signaling, cell volume regulation mechanisms as well as actin dynamics in astrocytes. While the nongliotic impact of P3HT:PCBM blend-based retinal implant has been demonstrated in situ, [87] the effect of P3HT:PCBM blend photostimulation in vivo as a gliophotonic interface for cortical astrocytes or for Müller glia in vivo has been completely unexplored.…”