Transient receptor potential vanilloid-4 channels are involved in diminished myogenic tone in brain parenchymal arterioles in response to chronic hypoperfusion in mice

Aim: Adaptive responses of brain parenchymal arterioles (PAs), a target for cerebral small vessel disease, to chronic cerebral hypoperfusion are largely unknown. Previous evidence suggested that transient receptor potential vanilloid 4 channels may be involved in the regulation of cerebrovascular tone. Therefore, we investigated the role of TRPV4 in adaptations of PAs in a mouse model of chronic hypoperfusion. Methods: TRPV4 knockout (^−/−) and wild-type (WT) mice were subjected to unilateral common carotid artery occlusion (UCCAo) for 28 days. Function and structure of PAs ipsilateral to UCCAo were studied isolated and pressurized in an arteriograph. Results: Basal tone of PAs was similar between WT and TRPV4^−/− mice (22 ± 3 vs 23 ± 5%). After UCCAo, active inner diameters of PAs from WT mice were larger than control (41 ± 2 vs 26 ± 5 μm, P < 0.05) that was due to decreased tone (8 ± 2 vs 23 ± 5%, P < 0.05), increased passive inner diameters (46 ± 3 vs 34 ± 2 μm, P < 0.05), and decreased wall-to-lumen ratio (0.104 ± 0.01 vs 0.137 ± 0.01, P < 0.05). However, UCCAo did not affect vasodilation to a small- and intermediate-conductance calcium-activated potassium channel agonist NS309, the nitric oxide (NO) donor sodium nitroprusside, or constriction to a NO synthase inhibitor L-NNA. Wall thickness and distensibility in PAs from WT mice were unaffected. In TRPV4^−/− mice, UCCAo had no effect on active inner diameters or tone and only increased passive inner diameters (53 ± 2 vs 43 ± 3 μm, P < 0.05). Conclusion: Adaptive response of PAs to chronic cerebral hypoperfusion includes myogenic tone reduction and outward remodelling. TRPV4 channels were involved in tone reduction but not outward remodelling in response to UCCAo.