15th Golgi lecture: from hyperglycaemia to the dysregulation of vascular remodelling in diabetes.
Hyperglycaemia has been shown to play a central part in diabetic vascular disease, which is also influenced by individual background. Hyperglycaemia initiates the pathogenetic sequence through a series of interrelated biochemical abnormalities, including increased flux through the polyol and hexosamine pathways, oxidative stress, AGE formation and protein kinase C activation. These abnormalities are capable of modifying the function of resident and non-resident vascular cells by changing their production pattern of several autocrine and paracrine factors, including growth, vasoactive and coagulation factors and adhesion molecules. These mediators profoundly impair the physiologic turnover of the vessel wall, thus leading to an abnormal process of vascular remodelling, with alterations in cell and matrix turnover and contacts, vascular tone and permeability and coagulation pattern. This process has distinct features depending on the target tissue. The hallmark of nephropathy is an abnormal accumulation of extracellular matrix within the mesangium, sustained by an upregulation of TGF-beta, possibly triggered by a local activation of the renin-angiotensin system. The central pathological lesion in retinopathy is retinal ischaemia due to the formation of acellular capillaries. The resulting vascular endothelial growth factor-dependent neovascularization is a detrimental phenomenon leading to the formation of noncompetent vessels. Conversely, in macrovascular disease, arterial occlusion 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 interrupting the pathogenetic sequence at the level of hyperglycaemia (and related biochemical events) are the most effective, whereas downstream interventions should be targeted to the tissue affected.
Di Mario
U
U
Dipartimento di Scienze Cliniche (Endocrinologia), La Sapienza University, Rome, Italy.
Pugliese
G
G
D000818:Animals; D001808:Blood Vessels / Q000473:pathology / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000097:blood / Q000503:physiopathology*; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology / Q000503:physiopathology*