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).
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).
|Suga, Hirotaka; Glotzbach, Jason P; Sorkin, Michael et al. (2014) Paracrine mechanism of angiogenesis in adipose-derived stem cell transplantation. Ann Plast Surg 72:234-41|
|Atashroo, David; Raphel, Jordan; Chung, Michael T et al. (2014) Studies in fat grafting: Part II. Effects of injection mechanics on material properties of fat. Plast Reconstr Surg 134:39-46|
|Wong, Victor W; Garg, Ravi K; Sorkin, Michael et al. (2014) Loss of keratinocyte focal adhesion kinase stimulates dermal proteolysis through upregulation of MMP9 in wound healing. Ann Surg 260:1138-46|
|Rennert, Robert C; Sorkin, Michael; Januszyk, Michael et al. (2014) Diabetes impairs the angiogenic potential of adipose-derived stem cells by selectively depleting cellular subpopulations. Stem Cell Res Ther 5:79|
|Chung, Michael T; Paik, Kevin J; Atashroo, David A et al. (2014) Studies in fat grafting: Part I. Effects of injection technique on in vitro fat viability and in vivo volume retention. Plast Reconstr Surg 134:29-38|
|Rennert, Robert C; Rodrigues, Melanie; Wong, Victor W et al. (2013) Biological therapies for the treatment of cutaneous wounds: phase III and launched therapies. Expert Opin Biol Ther 13:1523-41|
|Wong, Victor W; Sorkin, Michael; Gurtner, Geoffrey C (2013) Enabling stem cell therapies for tissue repair: current and future challenges. Biotechnol Adv 31:744-51|
|El-Ftesi, Samyra; Chang, Edward I; Longaker, Michael T et al. (2009) Aging and diabetes impair the neovascular potential of adipose-derived stromal cells. Plast Reconstr Surg 123:475-85|
|Hamou, Cynthia; Callaghan, Matthew J; Thangarajah, Hariharan et al. (2009) Mesenchymal stem cells can participate in ischemic neovascularization. Plast Reconstr Surg 123:45S-55S|
|Loh, Shang A; Chang, Edward I; Galvez, Michael G et al. (2009) SDF-1 alpha expression during wound healing in the aged is HIF dependent. Plast Reconstr Surg 123:65S-75S|
Showing the most recent 10 out of 12 publications