Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies

Abstract

Over the past two decades, extensive research has focused on arterial remodelling in both physiological and pathological ageing. The concept now describes the growth as well as the rearrangement of cellular components and extracellular matrix, resulting in either reduction or increase in vessel lumen. In diabetes, remodelling extends to capillaries, microvascular beds, and arteries of different calibre. This process is paralleled by accelerated atherosclerosis and accounts for an increased incidence of ischaemic complications. The incapacity of pre-existing and de novo formed collaterals to bypass atherosclerotic occlusions, combined with a decline in tissue capillary density, is responsible for the delayed recovery from ischaemia and ultimately leads to organ failure. The mechanisms of vascular remodelling are incompletely understood, but metabolic and mechanical factors seem to play an important role. Hyperglycaemia represents the main factor responsible for the fast progression of atherosclerosis as well as microangiopathy. However, intensive blood glucose control alone is insufficient to reduce the risk of macrovascular complications. Pharmacological control of oxidative stress and stimulation of nitric oxide release have proved to exert beneficial effects on vascular remodelling in experimental diabetic models. New approaches of regenerative medicine using vascular progenitor cells for the treatment of ischaemic disease have been shown to be safe and are now being tested for efficacy in pre-clinical and clinical trials.

Reactive oxygen species, reactive nitrogen species and antioxidants in etiopathogenesis of diabetes mellitus type-2

“…Allopurinol is an established drug to inhibit the activity of this enzyme and is commonly used to block the production of uric acid. The drug has been shown to reduce the OS in DMT-2 patients (15,50,73,74). Experimental studies have also corroborated these findings.…”

“…2 and subsequently several ROS are primarily responsible for mitochondrial dysfunction which play critical (42,67,73). There is growing evidence that NADPH oxidases are significant contributor of diabetic hypertension and that these enzymes play a contributory role in the pathogenesis of inflammation, hypertrophy, endothelium dysfunction, apoptosis, migration and renal remodeling in hypertension, angiogenesis and DMT-2 ( Fig 5) (42,73).…”

“…There is growing evidence that NADPH oxidases are significant contributor of diabetic hypertension and that these enzymes play a contributory role in the pathogenesis of inflammation, hypertrophy, endothelium dysfunction, apoptosis, migration and renal remodeling in hypertension, angiogenesis and DMT-2 ( Fig 5) (42,73). The effect of ROS on vascular cell growth, migration, proliferation and activation has been demonstrated by several workers (67,73). Notably, these diverse effects are mediated through redox sensitive regulation of multiple signaling molecules and second messengers including mitogen-activated protein kinases, protein tyrosine phosphatases, tyrosine kinases, proinflammatory genes, ionic calcium and ion channels.…”

“…2 instead of nitric oxide, resulting in heightened OS and reduced nitric oxide levels (94). Spinetti et al (73) have concluded from diabetic models that control of OS and increased production of nitric oxide have beneficial effects in DMT-2 but success of such studies has yet to be attempted and proven in humans.…”

“…Numerous clinical (5,15,42,43,54,62,73,(104)(105)(106)(107) and animal studies demonstrated that these are mainly due to chronic hyperglycemia intercalated by FR and OS (75- 79,108). Usually these complications set after several years of hyperglycemic condition.…”