Effective neovascularization, or new blood vessel formation, is critical for both wound healing and tissue survival following ischemia. Neovascularization occurs via two distinct pathways: the sprouting of new blood vessels from existing vessels (angiogenesis) and the recruitment, proliferation and assembly of bone-marrow derived vascular progenitor cells into new vessels (vasculogenesis). Through complex signaling mechanisms, ischemic tissue (the "soil") actively recruits circulating progenitor cells ("the seeds") out of the bone marrow and into the area of ischemia to initiate proliferation and differentiation of these cells into new blood vessels. We and others have shown that aging significantly impairs this communication between ischemic tissue and circulating progenitor cells and leads to dysfunctional vasculogenesis. In aged patients, this dysfunction hinders recovery from ischemic insults such as myocardial infarction or stroke and impairs wound healing, which leads to poor clinical outcomes. In this proposal, we will capitalize on our laboratory's expertise by focusing on impaired wound healing as a representative example of dysfunctional vasculogenesis in aging. During the prior funding period, we demonstrated that aging markedly diminishes the activity of the transcription factor hypoxia-inducible factor-1 alpha (HIF-1a), resulting in reduced expression of multiple vasculogenic genes and a dysfunctional response to ischemia. It is our fundamental hypothesis that dysfunction in HIF-1a-mediated neovascularization underlies the vascular complications of aging, and that identification and reversal of this dysfunction will improve recovery from ischemia in aged patients. In this proposal, we will expand on our previous findings to precisely define the causative mechanisms underlying HIF-1a dysfunction in hypoxic tissue (SA1), determine the role of increased oxidative stress in age-related dysfunctional vasculogenesis (SA2), and refine a therapeutic strategy to restore normal neovascularization to aged patients (SA3).

Public Health Relevance

Aging is a known risk factor for impaired wound healing and poor tissue recovery following an ischemic insult. Accordingly, advanced age is associated with a high risk of vascular comorbidities including cardiovascular disease, peripheral vascular disease, stroke, and vascular dementia. After myocardial infarction or stroke in aged patients, neovascularization is insufficient to properly rescue stunned myocardium or the central nervous system, thereby increasing morbidity and mortality. With a rapidly aging population in the United States, the population at risk for complications is expected to continue to grow. Ameliorating HIF-1a dysfunction in the aged would be expected to reduce morbidity and mortality in aged populations by improving the neovascularization response to ischemic events (e.g. myocardial infarction and stroke).

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AG025016-09
Application #
8658347
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kohanski, Ronald A
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Fujiwara, Toshihiro; Duscher, Dominik; Rustad, Kristine C et al. (2016) Extracellular superoxide dismutase deficiency impairs wound healing in advanced age by reducing neovascularization and fibroblast function. Exp Dermatol 25:206-11
Duscher, Dominik; Luan, Anna; Rennert, Robert C et al. (2016) Suction assisted liposuction does not impair the regenerative potential of adipose derived stem cells. J Transl Med 14:126
Duscher, Dominik; Atashroo, David; Maan, Zeshaan N et al. (2016) Ultrasound-Assisted Liposuction Does Not Compromise the Regenerative Potential of Adipose-Derived Stem Cells. Stem Cells Transl Med 5:248-57
Duscher, Dominik; Maan, Zeshaan N; Whittam, Alexander J et al. (2015) Fibroblast-Specific Deletion of Hypoxia Inducible Factor-1 Critically Impairs Murine Cutaneous Neovascularization and Wound Healing. Plast Reconstr Surg 136:1004-13
Rodrigues, Melanie; Wong, Victor W; Rennert, Robert C et al. (2015) Progenitor cell dysfunctions underlie some diabetic complications. Am J Pathol 185:2607-18
Duscher, Dominik; Neofytou, Evgenios; Wong, Victor W et al. (2015) Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proc Natl Acad Sci U S A 112:94-9
Chang, Edwin; Paterno, Josemaria; Duscher, Dominik et al. (2015) Exercise induces stromal cell-derived factor-1α-mediated release of endothelial progenitor cells with increased vasculogenic function. Plast Reconstr Surg 135:340e-50e
Wan, Derrick C; Gurtner, Geoffrey C; Longaker, Michael T (2015) Reply: Studies in fat grafting: part I. Effects of injection technique on in vitro fat viability and in vivo volume retention; and studies in fat grafting: part II. Effects of injection mechanics on material properties of fat. Plast Reconstr Surg 135:448e-9e
Tevlin, R; Atashroo, D; Duscher, D et al. (2015) Impact of surgical innovation on tissue repair in the surgical patient. Br J Surg 102:e41-55
Duscher, Dominik; Rennert, Robert C; Januszyk, Michael et al. (2014) Aging disrupts cell subpopulation dynamics and diminishes the function of mesenchymal stem cells. Sci Rep 4:7144

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