Date of Award

Spring 5-5-2023

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Lucy Liaw

Second Committee Member

Aaron Brown

Third Committee Member

Benjamin King

Additional Committee Members

Calvin Vary

Michaela Reagan

Abstract

Cardiovascular disease (CVD) is a leading cause of mortality globally. Metabolic diseases, such as obesity, are major risk factors for CVD development. Obesity changes adipose tissue physiology, thereby contributing to the establishment and progression of CVD. The perivascular adipose tissue (PVAT) is a unique depot that surrounds the vasculature. During obesity, PVAT secretes factors that induce vascular inflammation and contraction. Recent work has indicated a role for adipose-derived exosomes in regulating disease pathology. However, very little is known about the importance of PVAT-derived exosomes in modulating vascular health. Therefore, to study the importance of communication within the vascular microenvironment, Rab27a was selected for mutagenesis to induce the global loss of functional protein product within the mouse. RAB27A is a known regulator of exosome secretion due to its role in trafficking endosomal compartments to the plasma membrane. We hypothesize that RAB27A regulates paracrine signaling within the vascular microenvironment via exosome secretion.

Molecular, morphological, proteomic, and physiological approaches were used to determine whether the global loss of Rab27a altered the vascular microenvironment physiology. The data discussed herein provide evidence that a global loss of Rab27a uniquely impacts thoracic aorta contractile and dilative abilities for both male and female mice in an age-dependent manner. These observed changes in vessel contractility were supported through proteomic analysis and occur in the absence of gross morphological changes in the aorta and multiple adipose depots. The absence of morphological changes in the face of physiological adaptations suggest that global Rab27a loss causes a dysregulation of intercellular communication. Evidence of altered cellular communication is presented with proteomic studies suggesting that global loss of Rab27a alters exosome protein cargo. Furthermore, global loss of Rab27a during a high fat diet (HFD) exacerbates the physiological impact on male thoracic aorta by increasing contractile responses. Again, these observed changes in aorta physiology occur in the absence of altered morphology in both the PVAT and aorta. This work therefore provides a foundational study implicating the importance of Rab27a in the maintenance of vascular reactivity in connection to metabolic health.

Download

Files over 10MB may be slow to open. For best results, right-click and select "save as..."

Share