Role of Vascular Smooth Muscle Cell PiT-2 in Basal Ganglia Calcification
Chia, Jia Jun
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Idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative disorder that can be inherited in an autosomal dominant manner. The disease is characterized by bilateral calcium phosphate salt deposition primarily in the arterioles in the basal ganglia and thalamic region of the brain that result in symptoms such as vascular dementia, motor control disorders and strokes. However, there is currently no cure for IBGC. Recent genome studies have associated mutations in the gene that encodes a sodium-dependent phosphate (Pi) transporter, PiT-2, with approximately 50% of IBGC cases. PiT-2 is highly localized to vascular smooth muscle cells (VSMCs) in the cerebral vessels, and we hypothesized that PiT-2 in the VSMCs specifically plays a role in protecting VSMCs against calcification. In this research study, we developed an siRNA-based in vitro model in VSMCs to understand the etiology behind this disease. We observed a decrease in sodium-dependent Pi uptake levels but an increase in Pi-induced calcification following PiT-2 knockdown (KD), consistent with a protective role in VSMCs. Using PiT-2 KD VSMCs, we also investigated several mechanisms of vascular calcification and discovered that PiT-2 may normally inhibit cell death and maintain the level of calcification inhibitors. Based on previous studies showing that global PiT-2 haploinsufficient mice accurately recapitulated human BGC, an SM22α promoter-driven Cre knockout mouse model was developed for this study to investigate if PiT-2 in VSMCs were necessary for the inhibition of BGC. Characterization of the knockout mouse model showed that the deletion of PiT-2 in VSMCs is not sufficient to cause BGC, suggesting that VSMCs may not be the only cell type involved in the development of BGC. To our knowledge, this is the first mechanistic study investigating the role of VSMC PiT-2 in BGC, which is significant as it not only advances our understanding of the etiology underlying BGC, but also opens possibilities for developing therapeutics to target this disease.
- Bioengineering