Growth Factor Deregulation and Emerging Role of Phosphatases in Diabetic Peripheral Artery Disease

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.

Long Term Response to Circulating Angiogenic Cells, Unstimulated or Atherosclerotic Pre-Conditioned, in Critical Limb Ischemic Mice

“…Many of these metabolic alterations have been largely associated with insulin resistance and DM [ 77 , 78 , 79 ]. It is well known that DM greatly increases the incidence, progression, and severity of CLI [ 80 ]. Hyperglycemia affects the development of collateral arteries in response to ischemia and it also promotes down-regulation of proangiogenic factors together with impaired initiation of vascular angiogenesis [ 80 ], endothelial dysfunction, or higher inflammatory progression [ 81 , 82 , 83 , 84 ].…”

“…It is well known that DM greatly increases the incidence, progression, and severity of CLI [ 80 ]. Hyperglycemia affects the development of collateral arteries in response to ischemia and it also promotes down-regulation of proangiogenic factors together with impaired initiation of vascular angiogenesis [ 80 ], endothelial dysfunction, or higher inflammatory progression [ 81 , 82 , 83 , 84 ]. Furthermore, diabetic patients show dysfunctional CACs [ 85 ].…”

Diabetes Impaired Ischemia-Induced PDGF (Platelet-Derived Growth Factor) Signaling Actions and Vessel Formation Through the Activation of Scr Homology 2-Containing Phosphatase-1

“…PTPs have progressively emerged as potent players in growth factor unresponsiveness in vascular cells leading to the progression of several vascular complications of diabetes. 17 Previous studies have reported that hyperglycemia-induced modification of PTP expression or activity has been shown to deregulate the insulin, PDGFR-β, and VEGFR2 pathways contributing to nephropathy, 18 retinopathy, 16 or PAD. 19…”

Effect of Revascularization on Intramuscular Vascular Endothelial Growth Factor Levels in Peripheral Arterial Disease

“…Thus, a potential regulatory mechanism was absent in diabetics. Angiogenesis in diabetic PAD patients is impaired due to hyperglycemia [ 26 , 27 ]. In contrast, hypoglycemia is an inducer of the angiogenic switch [ 13 ].…”