Abstract 284: Lrp1 Regulates Smooth Muscle Contractility by Modulating Cytoskeletal Dynamics and Ca 2+ Signaling

Objective: Mutations affecting proteins in the extracellular matrix (ECM), microfibrils, or vascular smooth muscle cells (VSMCs) that impact contractility can predispose individuals to thoracic aortic aneurysms. We reported previously that the low-density lipoprotein receptor-related protein 1 (LRP1) maintains vessel wall integrity, and smooth muscle LRP1-deficient ( smLRP1 -/- ) mice exhibited aortic dilatation. The current study focused on the descending thoracic aorta (DTA) and examined the role of LRP1 in VSMC contractility and its potential effect on the vascular ECM. Approach and Results: LRP1-deficient VSMCs exhibited a synthetic phenotype characterized by higher proliferation rates and an increase in synthetic organelles, mitochondria, multivesicular bodies, and macropinocytotic vesicles. LRP1-deficient VSMCs also displayed changes in their microfilament and actin structure that result in an inadequate interaction with the ECM. Quantitative proteomics identified proteins involved in actin polymerization and contraction that were downregulated significantly in the DTA of smLRP1 -/- mice. Further analysis by qRT-PCR revealed attenuated mRNA levels for α-1D adrenergic receptor ( adra1d ) and calcium voltage-gated channel subunit α1 C ( cacna1c ) in smLRP1 -/- aortas. Isometric contraction assays confirmed aberrant contraction of smLRP1 -/- aortic rings when stimulated with vasoconstrictors. Furthermore, intracellular calcium imaging identified defects in response to a ryanodine receptor agonist in smLRP1 -/- aortic rings. Conclusions: These results suggest that LRP1 is required for maintaining the VSMC contractile phenotype and identifies a novel role for LRP1 in calcium homeostasis that potentially protects against aneurysm development.