Advisor(s)

Vivek Nanda

Committee Member(s)

Adam Wende
Brittany Lasseigne
C Miller
Pankaj Arora
Sara Cooper

Document Type

Dissertation

Date of Award

1-27-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Genetics

Abstract

Phenotypic switching of smooth muscle cells (SMCs) from a contractile to a synthetic state underlies the pathogenesis of several cardiovascular disease (CVD) pathologies, including restenosis and atherosclerosis. Leiomodin 1 (LMOD1), an SMC-enriched actin-binding protein, has been previously found to regulate SMC phenotypic modulation in vitro. However, its contribution to CVD development and progression, along with its influence on gene regulatory networks (GRNs) that inform underlying responses to stress, remains incompletely defined. Here, I combine a mouse injury model, bulk RNA sequencing, and GRN inference to define how reduced LMOD1 expression perturbs SMC physiology during vascular wall remodeling and lipid stress. In a carotid artery ligation model, Lmod1+/- mice developed significantly larger neointimal lesions, accompanied by increased SMC proliferation, consistent with a synthetic SMC phenotype. RNA sequencing and differential expression analyses highlighted cell cycle programs, with CDK6 as a key player in this phenotype. Functional studies showed that dual knockdown of LMOD1 and CDK6 restored proliferation toward baseline, implicating an LMOD1-CDK6 axis in neointimal lesion growth. Given that reduced LMOD1 amplified proliferative remodeling, I next asked whether the same deficit perturbs SMC lipid handling under atherogenic stress in cultured cells by exposing LMOD1-deficient SMCs to Dil-labeled oxidized low-density lipoprotein (oxLDL). Interestingly, LMOD1 deficiency increased oxLDL uptake and intracellular lipid accumulation. An interaction-term RNA-sequencing design isolated a focused gene set enriched for cholesterol homeostasis, with selective ABCA2 downregulation validated by quantitative RT-PCR. GRN analysis using PANDA/LIONESS revealed that loss of LMOD1 blunts the canonical oxLDL regulatory response and redirects the GRN to a distinct oxLDL-conditioned state, consistent with a loss of regulatory buffering that favors cholesterol retention and foam-cell-like persistence. Together, these studies establish complementary roles for LMOD1 in constraining SMC proliferation after injury and stabilizing transcriptional networks during lipid stress. They identify CDK6 as a candidate effector of neointimal hyperplasia, suggest ABCA2-associated cholesterol-handling pathways as selectively vulnerable to LMOD1 knockdown, and demonstrate that GRN-level rewiring captures disease-relevant phenotypes beyond differential expression alone. These findings advance a mechanistic framework in which preserving LMOD1 function, and/or targeting downstream nodes such as CDK6 and cholesterol-efflux programs, could mitigate SMC-driven vascular remodeling.

Keywords

atherosclerosis;CDK6;gene regulatory networks;leiomodin 1;neointimal hyperplasia;smooth muscle cell

ProQuest Publication Number

32283377

ISBN

9798273381100

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