Dr. Julie Phillippi is Assistant Professor of Cardiothoracic Surgery (primary appointment) and Bioengineering (secondary appointment). PhD (Biological Sciences), Carnegie Mellon University, 2005. Dr. Phillippi’s research scope broadly encompasses cell-extracellular matrix (ECM) dynamics using tissue-engineered approaches to study, diagnose and treat cardiovascular disease. Of immediate interest is the presence of local stem cells within distinct microenvironments of the aorta and their contribution to the development and progression of aortic aneurysm. Dr. Phillippi’s projects are carried out using human aortic tissue specimens and cell populations isolated from surgical patients of the Center for Thoracic Aortic Disease at the University of Pittsburgh Medical Center. Dr. Phillippi and her colleagues within the Thoracic Aortic Disease Research Laboratory are working to characterize the influence of distinct cell populations within the ascending aorta and the role of oxidative stress pathways on aortic wall architecture, strength and propensity for aortic disease. The ultimate goal of her work is to establish novel diagnostics and risk mitigation for patients affected by thoracic aortic disease and to develop new less-invasive treatment options that aim to prevent dilatation and/or invoke reverse remodeling of the aortic wall. Dr. Phillippi is affiliated faculty of the McGowan Institute for Regenerative Medicine and the Center for Vascular Remodeling and Regeneration. For more information, visit http://www.mirm.pitt.edu/thoracicaorticresearch
Title of Abstract
Human ascending aortic aneurysm pathophysiology involves elastin degeneration, and loss of smooth muscle cells in the media provoked by mechanisms that are mostly unknown. We recently uncovered down-regulation of several key pro-angiogenic factors in the adventitia from aneurysmal aortic specimens. In this study, we investigated the role of the adventitial microvascular network (vasa vasorum) and hypothesized that the vasa vasorum is disrupted in patients with ascending aortic aneurysm and is associated with medial hypoxia. Morphometric analyses of hematoxylin and eosin-stained human aortic cross-sections revealed evidence of vasa vasorum remodeling in aneurysmal specimens, including reduced density of small (<50 µm) vessels, increased lumen area and thickening of smooth muscle actin-positive layers. Gene expression of hypoxia-inducible factor 1α and its downstream targets, vascular endothelial growth factor and metallothionein 1A, were down regulated in the adventitia of aneurysmal specimens when compared with non-aneurysmal specimens. Immunodetection of glucose transporter 1, a marker of chronic tissue hypoxia, revealed minimal expression in non-aneurysmal specimens and high local accumulation within regions of medial elastin degeneration in aneurysmal specimens. This was accompanied with increased protein expression of glucose transporter 1 in the media of aneurysmal specimens when compared to non-aneurysmal specimens. These data reveal vasa vasorum remodeling in the aortic adventitia of patients with thoracic aortic aneurysm, associated down-regulation of angiogenic and hypoxia-related gene targets in the adventitial layer and evidence of chronic hypoxia in the aortic media. The noted vasa vasorum remodeling, coupled with deficiency of pro-angiogenic gene targets in the adventitia could contribute to medial degeneration through malnourishment of the aortic media, and a compromised ability to undergo vasculogenesis in the adventitia.
Marie Billaud1-4, Jennifer C. Hill1, Tara D. Richards1, Jeffrey Nine5, Thomas G. Gleason1-4 and Julie A. Phillippi 1-4
All Author Affiliations
Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA (1); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (2); Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA (3); Center for Vascular Remodeling and Regeneration, University of Pittsburgh, Pittsburgh, PA (4); Department of Pathology, University of Pittsburgh, Pittsburgh, PA (5)