Angiogenesis, Arteriogenesis, and Mitochondrial Dysfunction
Angiogenesis and arteriogenesis are key processes involved in the response to occlusive arterial disease and the pathology of cancer. Angiogenesis remodels the circulatory bed by new capillary formation, while arteriogenesis remodels existing arterioles b
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Angiogenesis, Arteriogenesis, and Mitochondrial Dysfunction M.S. McMurtry
Abstract Angiogenesis and arteriogenesis are key processes involved in the response to occlusive arterial disease and the pathology of cancer. Angiogenesis remodels the circulatory bed by new capillary formation, while arteriogenesis remodels existing arterioles by increasing their diameter. The main molecular mechanism of angiogenesis is initiation by activation of hypoxia-inducible factor (HIF)-1, and arteriogenesis, initiated mainly by shear stress, is modulated by HIF-1 activation. Mitochondria can modulate HIF-1 activation by release of mitochondrial reactive oxygen species and alpha-ketoglutarate, a required cofactor for prolyl hydroxylation and destruction of HIF components, and thus, mitochondria can influence HIF-1-dependent angiogenesis and arteriogenesis. Mitochondria may serve as metabolic sensors that link metabolic derangements to appropriate neovascularization in health and in chronic ischemia and inappropriate neovascularization in the context of cancer. Mitochondrial remodeling or dysfunction may impair angiogenesis and contribute to the pathology of diseases, including diabetes and myocardial dysfunction. Drugs that alter mitochondrial function may alter HIF-1-dependent neovascularization and may represent novel therapies for chronic ischemic diseases and cancer. Keywords Angiogenesis • Arteriogenesis • Neovascularization • Mitochondria
M.S. McMurtry, M.D., Ph.D., F.R.C.P.C. (*) Department of Medicine, University of Alberta, 8440 112th Street, Edmonton, AB, Canada T6G 2B7 e-mail: [email protected] B.I. Jugdutt and N.S. Dhalla (eds.), Cardiac Remodeling: Molecular Mechanisms, Advances in Biochemistry in Health and Disease 5, DOI 10.1007/978-1-4614-5930-9_15, © Springer Science+Business Media New York 2013
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M.S. McMurtry
Background: The Treatment Gap for Chronic Ischemic Diseases
Treatments for chronic refractory ischemia are needed for large numbers of patients that have failed conventional therapy. Cardiovascular diseases, including coronary disease (CAD), cerebrovascular, and lower extremity peripheral arterial disease (PAD), are leading causes of mortality and morbidity worldwide and in Canada [1–3]. Despite advances in medical therapy and revascularization, 10% of coronary artery disease patients have chronic refractory angina [4, 5], and 20–30% of critical limb ischemia patients need amputation [6]. Amputation rates for critical limb ischemia reach 1 per thousand of the general population [7–9], and the annual risk of amputation for those with PAD is approximately 1% [10]. New methods to revascularize ischemic tissues represent an important clinical need.
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Neovascularization: A Therapeutic Target
Targeting innate mechanisms of vascular remodeling and repair, including angiogenesis and arteriogenesis, is an attractive but elusive therapeutic strategy. Three processes of new blood vessel development in humans have been described, including angiogenesis, arteriogenesis, and vasculogenesis [11–1
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