Understanding regulatory pathways of neovascularization in diabetes

Abstract

Diabetes mellitus and its associated comorbidities represent a significant health burden worldwide. Vascular dysfunction is the major contributory factor in the development of these comorbidities, which include impaired wound healing, cardiovascular disease and proliferative diabetic retinopathy. While the etiology of abnormal neovascularization in diabetes is complex and paradoxical, the dysregulation of the varied processes contributing to the vascular response are due in large part to the effects of hyperglycemia. In this review, we explore the mechanisms by which hyperglycemia disrupts chemokine expression and function, including the critical hypoxia inducible factor-1 axis. We place particular emphasis on the therapeutic potential of strategies addressing these pathways; as such targeted approaches may one day help alleviate the healthcare burden of diabetic sequelae.

Keywords::

• angiogenesis
• C-X-C motif chemokine ligand 12
• diabetes
• hypoxia inducible factor-1
• myocardial infarction
• neovascularization
• progenitor cell
• proliferative diabetic retinopathy
• vasculogenesis
• wound healing

Financial & competing interests disclosure

Funding for vascular biology research conducted in our laboratory has been provided by the Hagey Family Endowed Fund in Stem Cell Research and Regenerative Medicine, the Armed Forces Institute of Regenerative Medicine (United States Department of Defense), the National Institutes of Health (R01-DK074095, R01-EB005718 and R01-AG025016), and the Oak Foundation. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Neovascularization, including both angiogenesis and vasculogenesis, is regulated by a complex signaling cascade and is critical for tissue repair and regeneration.

• Diabetes mellitus imbalances this signaling cascade leading to vascular dysfunction, evidenced either through diminished neovascularization in response to injury or ischemia or unneeded and excessive neovascularization, most commonly reported in the setting of proliferative diabetic retinopathy.

• Hyperglycemia is the major effector of diabetic vascular dysfunction, increasing oxidative stress and producing advanced glycation end products.

• Dysfunction of the hypoxia inducible factor-1α axis, with subsequent changes in VEGF and C-X-C motif chemokine ligand 12 expression, is arguably the most critical factor in the development of the diabetic neovascularization phenotype.

• Mobilization and recruitment of progenitor cells to sites of ischemia, as well as subsequent engraftment and function, are all severely impaired by the effects of hyperglycemia.

• Therapies targeting the dysfunctional pathways of neovascularization in diabetes show promise, particularly hypoxia inducible factor-1α, VEGF, C-X-C motif chemokine ligand 12 and progenitor cell-based therapies, but further investigation of the underlying mechanisms governing these signaling pathways is needed.

Notes