Abstract

Hypertension is a primary driver of cardiovascular disease, leading to arterial stiffening and end-organ damage. A defining characteristic of hypertensive pathology is its regional heterogeneity. The descending thoracic aorta (DTA) is highly vulnerable to structural remodeling and stiffening, while the infrarenal abdominal aorta (IAA) often maintains relative biomechanical resilience in response to the same systemic hypertensive stimulus. While traditional research has focused on the intrinsic layers of the vessel wall, this dissertation investigates the role of the “fourth layer”, perivascular adipose tissue (PVAT), as a fundamental determinant of these regional disparities. We challenge the conventional view of white adipose tissue (WAT) as a purely deleterious or passive depot, proposing instead that PVAT which exists as a mixture of brown adipose tissue (BAT) and WAT, serves as a dynamic, spatially resolved immune-metabolic-mechanical switch that governs vascular health. The first phase of this work identifies adaptive immunity as a “spatial governor” of vascular dysfunction. Using Angiotensin II-infused wild-type and lymphocyte-deficient (Rag1-/-) mice, we demonstrate that T cells drive pathological wall thickening and pro-inflammatory secretome shifts in the thoracic niche while simultaneously restraining a protective metabolic browning program in the abdominal niche. The absence of T cells unmasks a latent abdominal adaptation characterized by Pparg/Adipoq activation and enhanced vascular compliance, establishing PVAT as a critical regulator of regional vulnerability. Next, we mechanistically explore how regional adipose secretomes reprogram the vascular microenvironment through paracrine signaling. By integrating secretome profiling with traction force microscopy, we show that thermogenic thoracic PVAT (T-PVAT) depots promote a pro-fibrogenic fibroblast phenotype characterized by enhanced extracellular matrix synthesis and cellular stiffening. Crucially, we identify the RAGE-DPP4 signaling axis as a T-PVAT-specific mediator of fibroblast activation, which can be pharmacologically attenuated to mitigate perivascular fibrosis. Finally, we establish a new biomechanical framework to distinguish the roles of PVAT mass versus phenotype. Through genetic adipocyte ablation and pharmacological browning, we reveal that the DTA functions as a PVAT-dependent structure, relying on total PVAT for structural compliance and axial stretch. In contrast, the IAA is phenotype-dependent, exhibiting high sensitivity to perivascular signals and displaying a “mechanical trade-off” between circumferential and axial fiber loading when its adipose constraint is removed. Collectively, this research redefines hypertensive vascular remodeling as a disorder of immune-mechano-metabolic integration. By demonstrating that WAT provides essential mechanical buffering and metabolic plasticity, this work provides a foundation for spatially resolved, PVAT-targeted therapeutic strategies to preserve aortic compliance and treat cardiovascular disease.

Committee Chair

Matthew Bersi

Committee Members

Amit Pathak; Gretchen Meyer; Jessica Wagenseil; Jianjun Guan

Degree

Doctor of Philosophy (PhD)

Author's Department

Mechanical Engineering & Materials Science

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

6-22-2026

Language

English (en)

Download

Available for download on Monday, June 19, 2028

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