miR-137 and its target T-type Ca 3.1 channel modulate dedifferentiation and proliferation of cerebrovascular smooth muscle cells in simulated microgravity rats by regulating calcineurin/NFAT pathway.

OBJECTIVES

Postflight orthostatic intolerance has been regarded as a major adverse effect after microgravity exposure, in which cerebrovascular adaptation plays a critical role. Our previous finding suggested that dedifferentiation of vascular smooth muscle cells (VSMCs) might be one of the key contributors to cerebrovascular adaptation under simulated microgravity. This study was aimed to confirm this concept and elucidate the underlying mechanisms.

MATERIALS AND METHODS

Sprague Dawley rats were subjected to 28-day hindlimb-unloading to simulate microgravity exposure. VSMC dedifferentiation was evaluated by ultrastructural analysis and contractile/synthetic maker detection. The role of T-type Ca 3.1 channel was revealed by assessing its blocking effects. MiR-137 was identified as the upstream of Ca 3.1 channel by luciferase assay and investigated by gain/loss-of-function approaches. Calcineurin/nuclear factor of activated T lymphocytes (NFAT) pathway, the downstream of Ca 3.1 channel, was investigated by detecting calcineurin activity and NFAT nuclear translocation.

RESULTS

Simulated microgravity induced the dedifferentiation and proliferation in rat cerebral VSMCs. T-type Ca 3.1 channel promoted the dedifferentiation and proliferation of VSMC. MiR-137 and calcineurin/NFATc3 pathway were the upstream and downstream signalling of T-type Ca 3.1 channel in modulating the dedifferentiation and proliferation of VSMCs, respectively.

CONCLUSIONS

The present work demonstrated that miR-137 and its target T-type Ca 3.1 channel modulate the dedifferentiation and proliferation of rat cerebral VSMCs under simulated microgravity by regulating calcineurin/NFATc3 pathway.