Chronic hyperglicemia and nitric oxide bioavailability play a pivotal role in pro-atherogenic vascular modifications

Abstract

Diabetes is associated with accelerated atherosclerosis and macrovascular complications are a major cause of morbidity and mortality in this disease. Although our understanding of vascular pathology has lately greatly improved, the mechanism(s) underlying enhanced atherosclerosis in diabetes remain unclear. Endothelial cell dysfunction is emerging as a key component in the pathophysiology of cardiovascular abnormalities associated with diabetes. Although it has been established that endothelium plays a critical role in overall homeostasis of the vessels, vascular smooth muscle cells (vSMC) in the arterial intima have a relevant part in the development of atherosclerosis in diabetes. However, high glucose induced alterations in vSMC behaviour are not fully characterized. Several studies have reported that impaired nitric oxide (NO) synthesis and/or actions are often present in diabetes and endothelial dysfunction. Furthermore, although endothelial cells are by far the main site of vascular NO synthesis, vSMC do express nitric oxyde synthases (NOSs) and NO synthesis in vSMC might be important in vessel's function. Although it is known that vSMC contribute to vascular pathology in diabetes by their change from a quiescent state to an activated proliferative and migratory phenotype (termed phenotypic modulation), whether this altered phenotypic modulation might also involve alterations in the nitrergic systems is still controversial. Our recent data indicate that, in vivo, chronic hyperglycemia might induce an increased number of vSMC proliferative clones which persist in culture and are associated with increased eNOS expression and activity. However, upregulation of eNOS and increased NO synthesis occur in the presence of a marked concomitant increase of O(2-) production. Since NO bioavailabilty might not be increased in high glucose stimulated vSMC, it is tempting to hypothesize that the proliferative phenotype observed in cells from diabetic rats is associated with a redox imbalance responsible quenching and/or trapping of NO, with the consequent loss of its biological activity. This might provide new insight on the mechanisms responsible for accelerated atherosclerosis in diabetes.

Fig. 1

Schematic and simplified representation of endothelial function. Please see text for details. EC indicates endothelial cells; vSMC vascular smooth muscle cells; eNOS endothelial nitric oxide synthase, NO nitric oxide; VCAM-1 vascular cell adhesion molecule-1; ICAM-1 intercellular adhesion molecule-1; GTP guanosine 5′-triphosphate; GC guanylate cyclase; cGMP cyclic guanosine monophosphate; PKG protein kinase G

Fig. 2

Schematic and simplified representation of endothelial dysfunction. Please see text for details. EC indicates endothelial cells; vSMC vascular smooth muscle cells; eNOS endothelial nitric oxide synthase; iNOS inducible nitric oxide synthase; NO nitric oxide; VCAM-1 vascular cell adhesion molecule-1; ICAM-1 intercellular adhesion molecule-1; MCP-1 monocyte chemoattractant protein-1; NF-kB nuclear factor-kB; Nox NADPH-oxidase; ONOO⁻, peroxynitrates; BH4 tetrahydrobiopterin; PLA₂ phospholipase A₂; MPO myeloperoxidase; SR scavenger receptor; AngII angiotensin II; PDGF platelet-derived growth factor; bFGF, basic fibroblast growth factor; ROS reactive oxygen species; RNS reactive nitrogen species; ox-LDL oxidized low density lipoproteins

Fig. 3

Schematic overview of high glucose intracellular effects. Please see text for details. ROS indicates reactive oxygen species; PARP Poly ADP-Ribose Polymerase; GAPDH glyceraldehyde-3-phosphate dehydrogenase; PKC protein kinase C; AGEs advanced glycation product; NF-kB nuclear factor-kB; IRS-1 insulin receptor substrate-1; GSK-3β glycogen synthase kinase-3beta kinase; PI3-K phosphatidylinositol 3-kinase; eNOS endothelial nitric oxide synthase; HSP70 heat shock protein 70; VCAM-1 vascular cell adhesion molecule-1; ICAM-1 intercellular adhesion molecule-1; CREB CRE-binding protein; Egr-1 early growth response gene-1; PAI-1 plasminogen activator inhibitor-1; TGF-β transforming growth factor- β; ET-1 endothelin-1

Fig. 4

Schematic and simplified representation of glucose modified nitric oxide bioavailability and vascular smooth muscle cells behaviour. Please see text for details. ENOS indicates endothelial nitric oxide synthase; NO nitric oxide; ONOO⁻ peroxynitrates; O₂⁻ superoxide anion