SaaG e-Posters: Novel targets to regulate smooth muscle cells

086 - Vascular smooth muscle cell Orai1 in vascular health and disease (ID 374)

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Session Name
SaaG e-Posters: Novel targets to regulate smooth muscle cells
Presentation Topic
1.2 Smooth muscle cell biology
Presenter
Authors

Abstract

Background and Aims

Progression of atherosclerosis is associated with pathological remodelling of native vascular smooth muscle cells (VSMC) driven by platelet-derived growth factor (PDGF) signalling and subsequent activation of the calcium ion channel, Orai1. The quest now is for strategies to specifically target Orai1 channels and for comprehensive analysis of the impact of Orai1 dysfunction on vascular physiology and pathology.

Methods

We developed novel small-molecule Orai1 inhibitor and investigated its functional effects on human primary VSMC. RNA-Seq analysis was employed to characterise transcriptional changes associated with Orai1 inhibition. In vivo experiments investigated the effects of constitutively and inducibly deleted VSMC Orai1 on vascular pathophysiology.

Results

The novel small-molecule Orai1 inhibitor showed significantly potent and specific inhibition of store-operated calcium entry through Orai1 channels which restricted the PDGF-induced motility and proliferation of VSMC in vitro. RNA-Seq transcriptome profiling in VSMC revealed changes in transcriptional networks involved in cardiovascular diseases and lipid metabolism associated with Orai1 inhibition. Then, novel murine models with VSMC-specific Orai1 deletion from gestation or in adult VSMC were generated and studied. Interestingly, deletion of VSMC Orai1 either prenatally or in mature developed vessels from 8 weeks of age did not affect physiological remodelling as shown in the phenotypically normal developmental angiogenesis and normal vascular physiology, including blood pressure, morphology and distensibility of developed vessels. The effect of Orai1 inhibition in pathological remodelling in atherosclerosis was then examined using VSMC lineage-tracing murine models.

Conclusions

Our results provide novel insight into the role of Orai1 in VSMC remodelling and highlight potential target for pathologic remodelling without compromising the physiological remodelling.

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