Expression of leptin receptor (Ob-R) in human atherosclerotic lesions: potential role in intimal neovascularization

Abstract

Neovascularization of the adventitial vasa vasorum with extension into the intima of atherosclerotic lesions is frequently observed, but its pathophysiological significance is still subject to debate. Recently, leptin, the product of the Ob gene, was identified. Leptin, via activation of the endothelial receptor (Ob-R), generates a growth signal involving a tyrosine kinase-dependent intracellular pathway and promotes angiogenic processes. We hypothesized that a high concentration of leptin within vasa vasorum and plaque itself, may influence inflammatory and vascular neovascularization coupling with functional upregulation of the vascular endothelial growth factor (VEGF). Microscopic computerized tomography was utilized for the spatial distribution of vasa vasorum and intimal neovascularization from atherosclerotic human coronary arteries. Atherosclerotic coronary arteries showed a dense plexus of microvessels in the adventitia and plaque itself. Microscopic analysis from human atherosclerotic aortas revealed an increase in the intimal thickness with neovascularization. The immunoreactivity for Ob-R, VEGF and matrix metalloproteinase (MMP) increased in atherosclerotic plaque, predominantly in the endothelial lining of the intimal neovessel and macrophages/foam cells. Our observation of a prominent colocalization between Ob-R, VEGF and MMP supports this hypothesis and these factors participate in the neovascularization of atherosclerotic lesions. The present study is the first report on vascular tissue and it opens a promising perspective concerning future investigations of leptin-dependent modulation of atherogenesis and vascular neovascularization under pathophysiolgical conditions.

Influence of Leptin on Arterial Distensibility

“…Our study in healthy adolescents suggests a marked influence of leptin on arterial distensibility. This observation, together with evidence from experimental models [15][16][17][18][19][20] and from prospective studies that show an influence of leptin on clinical outcomes, 32,33 strongly suggests that leptin is one mechanism by which body fatness is linked to the early stages of atherosclerosis.…”

“…[15][16][17][18][19][20] Although predominantly involved in the hypothalamic control of body weight, leptin receptors are widely distributed on endothelial cells, [15][16][17] on other arterial wall subpopulations, 19 and on atherosclerotic lesions. 18,19 An action of leptin via these receptors may stimulate smooth muscle cell proliferation and migration, 20 whereas prolonged treatment with leptin has been shown to increase vascular cell calcification. 19 Leptin has also been shown to induce oxidative stress in endothelial cells, which could contribute to vascular pathology.…”

“…13,14 However, the widespread distribution of functioning leptin receptors on vascular cells suggests that leptin also plays an important role in vascular physiology. [15][16][17][18][19][20] In experimental models, leptin has been shown to have angiogenic activity, 15,16 increase oxidative stress in endothelial cells, 17 and to promote vascular cell calcification 19 and smooth muscle cell proliferation and migration. 20 Leptin's role linking fat mass and atherogenesis is supported by findings in the ob/ob mouse, which lacks a functioning leptin gene.…”

An Evaluation and Correlation of Leptin in Gingival Crevicular Fluid and Serum in Health, Gingivitis and Periodontitis

“…Hence, serum leptin concentrations were positively correlated with the periodontal disease progression. It has been suggested that rise in serum leptin concentration acts as a risk factor for cardiovascular diseases as it promotes atherosclerosis by enhancing platelet aggregation, 6 neovascularization of atherogenic plaque, 7 induction of oxidative stress in arterial wall 8 and also acceleration of hepatic degradation and clearance of high density lipoprotein (HDL) apoproteins. 9 Further, it induces calcification of arterial walls, thereby losing elasticity (distensibility), making them stiffer.…”

Transcriptional Activation by Hypoxia and Low-Density Lipoprotein Loading in Cultured Vascular Smooth Muscle Cells

“…Leptin gene expression has been reported in adipocytes, fibroblasts and various other cell types, yet the role of leptin in vascular SMCs is unknown. Leptin receptors have been reported to be widely distributed on endothelial cells [21][22][23] and other arterial wall subpopulations 24) , and in atherosclerotic lesions 24,25) . One action of leptin via these receptors may be to stimulate smooth muscle cell proliferation and migration 26) , whereas prolonged treatment with leptin has been shown to increase vascular cell calcification 24) .…”