REVIEW ARTICLE doi: 10.1111/j.1463-1326.2006.00655.x Diabetes-associated macrovasculopathy: pathophysiology and pathogenesis Sayeeda Rahman, 1 Tahminur Rahman, 2 Aziz Al-Shafi Ismail 3 and Abdul Rahman A. Rashid 4 1 Department of Pharmacology, School of Medical Sciences, Kubang Kerian, University Sains Malaysia, Kelantan, Malaysia 2 Department of Pathology, School of Medical Sciences, Kubang Kerian, University Sains Malaysia, Kelantan, Malaysia 3 Department of Community Medicine, School of Medical Sciences, Kubang Kerian, University Sains Malaysia, Kelantan, Malaysia 4 Advance Medical and Dental Institute, University Sains Malaysia, Penang, Malaysia The complications associated with diabetic vasculopathy are commonly grouped into two categories: microvascular and macrovascular complications. In diabetes, macrovascular disease is the commonest cause of mortality and mor- bidity and is responsible for high incidence of vascular diseases such as stroke, myocardial infarction and peripheral vascular diseases. Macrovascular diseases are traditionally thought of as due to underlying obstructive atherosclerotic diseases affecting major arteries. Pathological changes of major blood vessels leading to functional and structural abnormalities in diabetic vessels include endothelial dysfunction, reduced vascular compliance and atherosclerosis. Besides, advanced glycation end product formation interacts with specific receptors that lead to overexpression of a range of cytokines. Haemodynamic pathways are activated in diabetes and are possibly amplified by concomitant systemic hypertension. Apart from these, hyperglycaemia, non-enzymatic glycosylation, lipid modulation, alteration of vasculature and growth factors activation contribute to development of diabetic vasculopathy. This review focuses on pathophysiology and pathogenesis of diabetes-associated macrovasculopathy. Keywords: diabetes, diabetic vasculopathy, macrovasculopathy Received 5 January 2006; returned for revision 21 June 2006; revised version accepted 19 July 2006 Introduction Diabetes mellitus is a multifactorial disease associated with a number of microvascular (retinopathy, neuropathy and nephropathy) and macrovascular (ischaemic heart disease, cerebrovascular disease and peripheral vascular diseases) complications [1–3]. Diabetic macrovasculop- athy is associated with structural and functional changes in large arteries that lead to increased stiffness, abnormal pulse wave travel and systolic hypertension. Structural changes result mainly from glycation of wall components and functional changes originate in endothelial dysfunc- tion, increased arterial stiffness or decreased arterial dis- tensibility. These structural and functional changes lead to increase pulse wave velocity and the amplitude of reflected waves, which in turn causes early arrival of reflected waves augmenting central systolic pressure. This promotes the development of left ventricular hyper- trophy, an independent risk factor for cardiovascular (CV) mortality [4]. Apart from the above-mentioned mechanisms, metabolic [advanced glycation end produc- tion (AGE), cytokines], humoral (renin–angiotensin sys- tem, endothelin, sympathetic nervous system) and haemodynamic (arterial hypertension and mechanical Correspondence: Sayeeda Rahman, Department of Pharmacology, School of Medical Sciences, University Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia. E-mail: seempi2005@yahoo.co.uk # 2006 The Authors Journal Compilation # 2006 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 9, 2007, 767–780 j 767