15(th) Golgi lecture: from hyperglycaemia to the dysregulation of vascularremodelling in diabetes

Hyperglycaemia has been shown to play a central part in diabetic vascular d isease, which is also influenced by individual background. Hyperglycaemia i nitiates the pathogenetic sequence through a series of interrelated biochem ical abnormalities, including increased flux through the polyol and hexosam ine pathways, oxidative stress, AGE formation and protein kinase C activati on. These abnormalities are capable of modifying the function of resident a nd non-resident vascular cells by changing their production pattern of seve ral autocrine and paracrine factors, including growth, vasoactive and coagu lation factors and adhesion molecules. These mediators profoundly impair th e physiologic turnover of the vessel wall, thus leading to an abnormal proc ess of vascular remodelling, with alterations in cell and matrix turnover a nd contacts, vascular tone and permeability and coagulation pattern. This p rocess has distinct features depending on the target tissue. The hallmark o f nephropathy is an abnormal accumulation of extracellular matrix within th e mesangium, sustained by an upregulation of TGF-beta, possibly triggered b y a local activation of the renin-angiotensin system. The central pathologi cal lesion in retinopathy is retinal ischaemia due to the formation of acel lular capillaries. The resulting vascular endothelial growth factor-depende nt neovascularization is a detrimental phenomenon leading to the formation of noncompetent vessels. Conversely, in macrovascular disease, arterial occ lusion resulting from plaque formation with superimposed thrombosis elicits an angiogenic response which is impaired, but generates competent vessels, potentially compensating for reduced flow Thus, upstream interventions int errupting the pathogenetic sequence at the level of hyperglycaemia land rel ated biochemical events) are the most effective, whereas downstream interve ntions should be targeted to the tissue affected.