HIF-1 and Age-Related Impairment of Neovascularization in Regeneration

Hypoxia inducible factor 1 (HIF-1) is known to be important in skin aging, involved in the regulation of numerous processes relevant to the maintenance and structure of skin tissue. One of these is the growth of blood vessels that is required for regeneration to take place following injury. The dysfunction of HIF-1 signaling and consequent dysfunction in blood vessel regrowth is a feature of the varieties of non-healing wounds that are observed in older people. The open access paper here reviews what is known of HIF-1 in this context.

Oxygen is key to many processes of life and is involved in all stages of wound healing in the skin, with many cells and pathways being reactive to changes in oxygen concentration. Following injury to the skin, disruption of the vasculature results in a hypoxic environment, which is further exacerbated by high oxygen consumption through the cells present at the edge of the wound. Hypoxia has been found to have myriad effects on cells and their function, such as inducing greater dermal fibroblast proliferation and production of TGF-β1. Furthermore, hypoxia has been shown to promote in vitro keratinocyte motility and leads to the secretion of several growth factors. These are but a few of the many roles acute hypoxia plays in the induction of skin healing, and although hypoxia is necessary for regeneration, a return to normoxic conditions is eventually required.

With hypoxia being of such importance to regeneration of the skin, the HIF pathways have drawn much attention. Hypoxia-inducible factors (HIFs) are pleiotropic key regulators of oxygen homeostasis. HIF-1 consists of two subunits: HIF-1α (or its analogs HIF-2α and HIF-3α) and HIF-1β, which bind to acquire the transcriptional capabilities that promote cell survival during hypoxia. Additionally, HIF-1 serves as a crucial modulator in the homeostatic processes during hypoxia by increasing vascularization and regulating anaerobic respiration.

While HIF-1 is undoubtedly important for wound healing, excessive expression of HIF-1 can lead to unwanted fibroproliferation in the form of keloids and hypertrophic scarring. Conversely, deficits in HIF-1 signaling can lead to inadequate wound healing. Chronic wounds are often characterized by a constant, nonresolving inflammatory phase, causing proinflammatory signaling cascades to persist. This results in higher levels of proteases that work to destroy extracellular matrix components and other molecules beneficial to wound healing, preventing the proliferation and tissue remodeling phases from advancing normally. Studies have identified HIF-1 signaling as one of the underlying causes behind many nonhealing wounds. Common examples of chronic wounds include diabetic wounds, pressure ulcers, and aged wounds.

The structure and pathophysiology of aged skin differs greatly from the skin in younger individuals. These discrepancies are responsible for the delayed healing found in aged skin, many of which are the result of irregular HIF-1 signaling. Over the past decade, extensive studies have examined the expression levels of HIF-1 in the aged compared with the young, and how regeneration was affected. One of the major observations of aged wound healing is that there is significantly lesser neovascularization following ischemia, impeding recovery. Neovascularization in humans occurs through both angiogenesis, the sprouting of new vessels from old ones, and vasculogenesis, the formation of new vessels by migration and aggregation of endothelial progenitor cells.

HIF-1α signaling has been shown to regulate both of these processes through transcription of cytokines such as SDF-1α. An improved understanding of the regulation of molecular mediators, such as HIF-1α and PHD, will allow for manipulation of the various factors underlying delayed wound healing in the aged. The findings highlighted in this may facilitate the development of potential therapeutic approaches involved in the alteration of cellular dynamics and aging.


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