Joseph L

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     T551: Peripheral Circulation

Section of Vascular Surgery

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Research Interests:

      Arterial remodeling, collateral artery development and function, microvascular growth and remodeling, modulators of vascular growth, endothelial cell dysfunction, shear-mediated vascular remodeling.

Research Focus:

The current research projects in my laboratory are focused upon compensatory vascular adaptations in arterial occlusive disease and pathological adaptations which occur during advancing age.

Research from our group has indicated that the greatest compensatory adaptation to arterial occlusion occurs in small arteries and arterioles which form collateral pathways. Our studies suggest that the initiating stimuli for this collateral development are physical forces exerted upon the vessel wall by blood flow. Alterations in blood flow can influence gene expression, cell growth, and matrix metalloproteinase activity within the arterial wall. All of these processes are necessary for successful remodeling to form larger vessels. One of our long-term goals is to determine the mechanisms, molecules and processes which are involved in successful collateral development in young, normal animals.

The major risk factors for vascular occlusive disease (hypertension, diabetes, smoking, hypercholesterolemia, and aging) are all associated with endothelial dysfunction. Endothelial dysfunction is characterized by reduced bioavailability of nitric oxide and overproduction of superoxide ions. Our laboratory and others have shown that collateral artery development is significantly suppressed by endothelial dysfunction. At this time, a major emphasis of our lab group is to investigate how shear-mediated collateral development is suppressed by endothelial dysfunction.   By studying successful collateral development in young, healthy animals and the mechanisms responsible for impairment during endothelial dysfunction, we hope to accomplish our overall objective--enhance collateral development in the presence of vascular disease by restoring the natural capacity that is present in young healthy animals.

When endothelial dysfunction is present, pathological adaptations tend to occur in the vasculature; especially in larger arteries. We believe increased oxidative stress in the context of endothelial dysfunction induces a pro-inflammatory state which both promotes pathological remodeling and prevents compensatory remodeling such as collateral development. We are currently utilizing proteomic and genomic techniques to identify molecules and better understand mechanisms which are responsible for compensatory and pathological remodeling.

The following is taken from the abstract for our NIH grant on collateral artery development:

Recent studies in humans have shown a correlation between advancing age, hypertension, and diabetes and impairment of collateral function/development. Controversy currently exists regarding the mechanisms and molecules which mediate “normal” collateral development. Information on molecules and mechanisms responsible for impairment of collateral development is essentially nonexistent. Understanding normal regulatory processes of collateral development and how they are compromised in the presence of major risk factors for vascular disease is a current and long-term goal of this project.      Successful remodeling of the vascular wall requires controlled regulation of gene expression, vascular cell growth, and matrix metabolism. Superoxide (O2-) and nitric oxide (NO) and their daughter compounds are capable of inhibiting or promoting each of these processes. Studies related to 3 specific aims will determine the role of free radicals in 1) vascular cell growth, 2) gene expression, and 3) matrix metabolism during normal collateral development. Additional experiments within each aim will determine how increased oxidative stress and/or reduced NO bioavailability may impair collateral development.       An in vivo model which permits paired comparisons of collateral and control vessels within animals will be used. Spontaneously hypertensive rats (SHR) will be utilized as a model of endothelial dysfunction. Preliminary studies demonstrate that collateral luminal expansion is suppressed in SHR; that inhibition of the NO system mimics this suppression and that antioxidant therapy restores luminal expansion in SHR. In vivo and ex vivo methods will be used to quantify levels of NO and O2-. Specific enzymes, enzyme inhibitors, and free radical scavengers will be used to determine the role of NO and reactive oxygen species. Vascular cell proliferation and apoptosis will be evaluated with immunohistochemical techniques. Gene expression will be determined by real-time RT-PCR and immunoblotting and localized with the arterial wall with immunohistochemistry. Levels of latent and active matrix metalloproteinase will be determined with gel zymography, immunoblotting and immunohistochemistry.       These studies will clarify major mechanisms responsible for normal and impaired collateral growth and predict therapeutic approaches to enhance collateral enlargement.

URL: http://www.iuvascular.com/Unthank/Research/projects.html