Adventitial extracellular matrix from aneurysmal aorta fails to promote pericyte contractility Kaitlyn Wintrubaa, Bryant Fisherb, Jennifer C. Hillb, Tara D. Richardsb, Marie Billaudb-d, Amadeus Sternd, Thomas G. Gleasonb-d, Julie A. Phillippib-d Department of Chemical Engineering, bDepartment of Cardiothoracic Surgery, cDepartment of Bioengineering, d McGowan Institute for Regenerative Medicine University of Pittsburgh, Pittsburgh, PA, USA a
Kaitlyn Wintruba is in her second year at the Swanson School of Engineering where she studies Chemical Engineering. After graduating, Kaitlyn plans to pursue her interest in regenerative medicine and biomedical research in graduate school. Kaitlyn Wintruba
Dr. Julie Phillippi is Associate Professor with Tenure in the Department of Cardiothoracic Surgery, School of Medicine with a secondary appointment in the Department of Bioengineering Swanson School of Engineering. Dr. Phillippi’s research is focused on the role of Dr. Julie Phillippi perivascular progenitor cells, adventitial biology, and vasa vasorum function in human aortic disease. Her work is currently funded by the National Heart, Lung and Blood Institute under award # R01HL131632.
Significance Statement
Ascending thoracic aortic aneurysm (TAA) is a lifethreatening condition, for which there are no strategies for early intervention. Our work supports the use of an extracellular matrix hydrogel as a potential regenerative biomaterial in the setting of TAA and translation towards microvascular regeneration in clinical applications.
Category: Experimental research
Keywords: Pericyte, Extracellular Matrix Hydrogel, Adventitia, Aortic Aneurysm Abbreviations: thoracic aortic aneurysm (TAA), extracellular matrix (ECM), aortic adventitia (Adv), porcine aortic adventitia (pAdv), human aortic adventitia (hAdv), fibroblast growth factor 2 (FGF2), platelet derived growth factor (PDGF), vascular endothelial growth factor A (VEGF-A), transforming growth factor beta 1 (TGFβ1), dimethyl sulfoxide (DMSO)
106 Undergraduate Research at the Swanson School of Engineering
Abstract
Ascending thoracic aortic aneurysm (TAA) is a life-threatening condition lacking adequate diagnostics and risk adjudication for aortic dissection or rupture. Studying the adventitia, the outer most layer of the aorta, our group previously uncovered downregulation of several pro-angiogenic factors and reduced density of the microvascular network of vasa vasorum in aneurysmal aortic specimens. Knowledge of how adventitial extracellular matrix (ECM) influences the function of vasa vasorum-associated cells could potentially lead to developing a better diagnostics and therapies for TAA or aortic dissection. We hypothesized that adventitial ECM from normal aorta enhances pericyte function through a growth factor-mediated mechanism deficient in aneurysm-derived aortic adventitia. To test this hypothesis, we quantified pericyte contractility within a 3D hydrogel tissue culture scaffold as a measure of pericyte function. Human aortic adventitia (Adv)-derived pericytes were cultured within 2mg/mL bovine Type I collagen gels in the presence or absence of lyophilized human or porcine Adv ECMs. Addition of Adv ECMs to collagen accelerated gelation at 37˚C as evidenced by a higher optical density (p<0.05). Addition of normal human Adv ECM increased pericyte contractility when compared with aneurysm-derived Adv ECM (p<0.001). Inhibition of TGFβ-1R decreased porcine Adv ECM-induced contractility when compared with cells treated with vehicle and porcine Adv ECM (p<0.001). This work supports the use of porcine-derived ECM hydrogels to improve function of vasa vasorum-associated cells as a potential therapeutic biomaterial for microvascular regeneration in human aortic disease.
1. Introduction
Ascending thoracic aortic aneurysms (TAAs) are often asymptomatic, and the only treatment to prevent aortic dissection or rupture is elective replacement of the ascending aorta. Aortic dissection occurs in 5 to 30 cases per million of the population annually [1] with the mortality rates of aortic dissection worldwide being 1% per hour without surgical intervention [2]. Interactions between the cellular and extracellular matrix (ECM) components of the intimal, medial, and adventitial layers of the aorta mediate blood flow throughout the body. Currently, the complex cellular molecular mechanisms inciting TAA and driving disease progression remain incompletely understood. Improved understanding of these mechanisms could help develop less invasive treatment options. Prior work in the Thoracic Aortic Disease Research Laboratory identified involvement of the adventitial microenvironment in the pathogenesis of TAA. Growth factors within adventitial ECM such as fibroblast growth factor 2 (FGF2), platelet derived growth factor (PDGF), vascular endothelial growth factor A (VEGF-A) can influence vasa vasorum-associated cells. These pro-angiogenic growth factors involved with vasculogenic function were found to be downregulated in human aneurysmal aortic specimens and porcine-derived adventitial (pAdv) ECM exhibited FGF2-mediated angiogenic activity in vitro and in vivo [3]. Transforming growth factor beta (TGFβ) is involved in various vasculogenic functions
