Author ORCID Identifier


Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation


Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dianna M. Milewicz, M.D., Ph.D.

Committee Member

Jaroslaw Aronowski, M.D., Ph.D.

Committee Member

Ruth Heidelberger, M.D., Ph.D.

Committee Member

Louise McCullough, MD, PhD

Committee Member

Guang Peng, M.D., Ph.D.


Vascular diseases are a leading cause of morbidity and mortality world-wide. Understanding their pathogenesis is crucial to better diagnosis and management of these life-threatening conditions. Through the study of rare mutations that lead to early onset and severe vascular diseases, we can elucidate underlying mechanisms for vascular disease pathogenesis and develop better treatments to prevent and manage more common causes of vascular diseases. In this study we look at two rare diseases that lead to severe vascular phenotypes, Smooth Muscle Dysfunction Syndrome (SMDS) and Majewski Osteodysplastic Primordial Dwarfism Type II (MOPDII). SMDS is a rare condition due to pathogenic variants in ACTA2 p.Arg179, which lead to dysfunction of smooth muscle cells (SMCs) throughout the body. Complications of SMDS include early-onset thoracic aortic aneurysms and dissections, moyamoya-like cerebrovascular disease, patent ductus arteriosus, pulmonary hypertension and poorly characterized pulmonary disease, hypoperistalsis of the gut, hypotonic bladder, and congenital mydriasis. Here lung and liver pathology findings from two infants and one adult with SMDS are described, including thickening of the terminal branches of the hepatic artery and emphysematous pulmonary changes, along with previously described changes consistent with pulmonary arterial hypertension. These data provide further insight into the pathophysiology of complications of SMDS. MOPDII is due to homozygous loss-of-function mutations in PCNT, which lead to primordial dwarfism and early onset occlusive vascular disease, including moyamoya disease and coronary artery disease. We examine the pathogenic mechanisms of vascular disease in MOPDII using a novel SMC-specific pericentrin knock-out mouse line (PcntSMKO). Using this mouse model, we identify increased proliferation of SMCs explanted from the aortas of PcntSMKO mice and activation of the ataxia telangiectasia and rad3 related (ATR) cell cycle regulation pathway. Further, we identify phenotypic modulation of PcntSMKO SMCs in vitro to a phenotype similar to that observed with the progression of atherosclerosis in mice. The modulated cells express markers of both macrophages and fibroblasts, with a reduction in SMC identity markers. This phenotypic modulation in PcntSMKO SMCs is associated with activation of the unfolded protein response and cytosolic stress pathways. The findings presented here suggest potential mechanisms and future targets for vascular disease intervention.


pericentrin, smooth muscle actin, primordial dwarfism, cell cycle regulation