The Mechanism of Discoidin Domain Receptor 1 Mediated Vascular Calcification

Introduction: Activation of Runt Related Transcription Factor 2 (RUNX2) is required for transdifferentiation of Vascular Smooth Muscle Cells (VSMCs) into a calcifying osteoblast-like phenotype. Our lab showed that deletion of Discoidin Domain Receptor 1 (Ddr1), decreased atherosclerotic vascular calcification in the Ldlr-/- mouse. Hypothesis: DDR1 regulates RUNX2 activity by affecting microtubule organization during VSMC mediated calcification. Results: Ddr1-/- VSMCs show reduced RUNX2 activity when compared to Ddr1+/+ VSMCs. Addition of the microtubule-destabilizing agent nocodazole inhibited both RUNX2 activity and nuclear localization in Ddr1+/+ VSMCs. Addition of the microtubule-stabilizing agent taxol rescued RUNX2 nuclear localization in Ddr1-/- VSMCs. Despite this, Taxol was unable to rescue RUNX2 activity as it eliminated activity in both genotypes. Conclusion: These findings indicate that under osteogenic conditions, Ddr1 deletion impedes the dynamic instability required for the maintenance of microtubule architecture. This prevents RUNX2 nuclear localization and transcriptional activation in VSMCs.MAS