Abstract
Peripheral artery disease is caused by atherosclerosis of lower extremity arteries leading to the loss of blood perfusion and subsequent critical ischemia. The presence of diabetes mellitus is an important risk factor that greatly increases the incidence, the progression and the severity of the disease. In addition to accelerated disease progression, diabetic patients are also more susceptible to develop serious impairment of their walking abilities through an increased risk of lower limb amputation. Hyperglycemia is known to alter the physiological development of collateral arteries in response to ischemia. Deregulation in the production of several critical pro-angiogenic factors has been reported in diabetes along with vascular cell unresponsiveness in initiating angiogenic processes. Among the multiple molecular mechanisms involved in the angiogenic response, protein tyrosine phosphatases are potent regulators by dephosphorylating pro-angiogenic tyrosine kinase receptors. However, evidence has indicated that diabetes-induced deregulation of phosphatases contributes to the progression of several micro and macrovascular complications. This review provides an overview of growth factor alterations in the context of diabetes and peripheral artery disease, as well as a description of the role of phosphatases in the regulation of angiogenic pathways followed by an analysis of the effects of hyperglycemia on the modulation of protein tyrosine phosphatase expression and activity. Knowledge of the role of phosphatases in diabetic peripheral artery disease will help the development of future therapeutics to locally regulate phosphatases and improve angiogenesis.
Highlights
Current data reveals that more than 400 million people are suffering from diabetes mellitus (DM) and projections estimate that numbers of this world-wide issue will almost triple by 2030 [1]
Diabetic Peripheral artery disease (PAD) is characterized by insufficient angiogenesis of the lower extremities which is attributed to impaired production of pro-angiogenic factors and defects in signal transduction in both vascular and perivascular cells
Larger clinical studies supported by suitable preclinical mechanistic models are required to guide and optimize the development of new therapeutic targets based on the administration of exogenous growth factors which are currently lacking sustainable effects
Summary
The bibliographic search was performed in the PubMed and Google Scholar databases. All papers published before June 2020 were included in the review. A large set of keywords was used including growth factor, tyrosine kinase receptor, diabetic PAD, angiogenesis, blood flow reperfusion, endothelial dysfunction, endothelial cells, perivascular cells, hindlimb ischemia, phosphatase, and hyperglycemia
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