leptin and Corneal-Neovascularization

The metabolic syndrome in association with obesity is a major clinical problem inducing hypertension, diabetes mellitus, and atherosclerosis. Leptin induces angiogenesis by its proliferative effects on endothelial cells (ECs) via OB receptor (OB-Rb) gene. We evaluated the growth of ECs and intracellular signalings in response to leptin in vitro and the angiogenic effects of leptin in the cornea in vivo with and without adenovirus-mediated transfer of the OB-Rb gene in Zucker fatty (ZF) rats as a model for the metabolic syndrome. Recombinant adenovirus vector encoding rat OB-Rb (Ad.OB-Rb) or Escherichia coli. LacZ (Ad.LacZ) was transfected into cultured ECs from Zucker lean (ZL) rats and ZF rats. Leptin increased DNA synthesis dose-dependently in ECs from ZL rats but not ZF rats. Infection with Ad.OB-Rb, but not with Ad.LacZ, improved the growth effects of leptin in ECs from ZF rats. Leptin induced phosphorylation of Janus kinase (JAK)2, signal transducer and activator of transcription (STAT)3, and extracellular signal-regulated kinase (ERK) in ECs from ZL rats but not ZF rats. Infection with Ad.OB-Rb restored phosphorylation of JAK2 and STAT3 in ECs from ZF rats. Leptin induced angiogenesis in cornea from ZL rats, but not from ZF rats. Coadministration of leptin and Ad.OB-Rb induced angiogenesis in cornea from ZF rats. Ad.LacZ did not influence the angiogenic effects of leptin. The impaired endothelial function with the leptin resistance may be one of causes of the atherosclerosis in the metabolic syndrome.

Topics: Adenoviridae; Animals; Arteriosclerosis; beta-Galactosidase; Corneal Neovascularization; DNA; Endothelial Cells; Gene Transfer Techniques; Genetic Vectors; Leptin; Obesity; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transfection

Most endocrine hormones are produced in tissues and organs with permeable microvessels that may provide an excess of hormones to be transported by the blood circulation to the distal target organ. Here, we investigate whether leptin, an endocrine hormone, induces the formation of vascular fenestrations and permeability, and we characterize its angiogenic property in the presence of other angiogenic factors. We provide evidence that leptin-induced new blood vessels are fenestrated. Under physiological conditions, capillary fenestrations are found in the leptin-producing adipose tissue in lean mice. In contrast, no vascular fenestrations were detected in the adipose tissue of leptin-deficient ob/ob mice. Thus, leptin plays a critical role in the maintenance and regulation of vascular fenestrations in the adipose tissue. Leptin induces a rapid vascular permeability response when administrated intradermally. Further, leptin synergistically stimulates angiogenesis with fibroblast growth factor (FGF)-2 and vascular endothelial growth factor (VEGF), the two most potent and commonly expressed angiogenic factors. These findings demonstrate that leptin has another new function-the increase of vascular permeability.

Topics: Adipose Tissue; Animals; Capillaries; Capillary Permeability; Cattle; Cell Division; Cells, Cultured; Cornea; Corneal Neovascularization; Drug Synergism; Endothelial Growth Factors; Endothelium, Vascular; Female; Fibroblast Growth Factor 2; Humans; Leptin; Lymphokines; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Obese; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Leptin is a hormone that regulates food intake, and its receptor (OB-Rb) is expressed primarily in the hypothalamus. Here, it is shown that OB-Rb is also expressed in human vasculature and in primary cultures of human endothelial cells. In vitro and in vivo assays revealed that leptin has angiogenic activity. In vivo, leptin induced neovascularization in corneas from normal rats but not in corneas from fa/fa Zucker rats, which lack functional leptin receptors. These observations indicate that the vascular endothelium is a target for leptin and suggest a physiological mechanism whereby leptin-induced angiogenesis may facilitate increased energy expenditure.

Topics: Adipocytes; Amino Acid Sequence; Animals; Carrier Proteins; Cells, Cultured; Corneal Neovascularization; DNA-Binding Proteins; Endothelial Growth Factors; Endothelium, Vascular; Energy Metabolism; Humans; Leptin; Lipid Metabolism; Lymphokines; Molecular Sequence Data; Neovascularization, Physiologic; Phosphorylation; Proteins; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; STAT3 Transcription Factor; Trans-Activators; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors