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Zhao M.,Peking University | Zhao M.,Key Laboratory of Vision Loss and Restoration | Shi X.,Peking University | Shi X.,Key Laboratory of Vision Loss and Restoration | And 10 more authors.
Experimental Eye Research | Year: 2011

Retinopathy of prematurity (ROP) has become one of the leading causes of blindness and visual loss in children over the last half century. Vascular Endothelial growth Factor (VEGF-A) is the principal stimulator of angiogenesis. Recently, it has been identified that VEGF was differentially spliced from Exons 8 to Exons 8a and 8b to form two families: the pro-angiogenic VEGFxxx family and the anti-angiogenic VEGFxxxb family. This alternate splicing produced VEGFxxxb proteins of the same length as VEGFxxx family, but with different C terminal amino acid sequences. VEGFxxxb appeared to be able to inhibit VEGFxxx-dependent angiogenesis. In our study, we investigated the protein expression course of VEGFxxx and VEGFxxxb by Western-blot in a mouse model of Oxygen-induced Retinopathy (OIR) from postnatal day 1 (P1) to postnatal day 21 (P21). We also analyzed the relative protein expression level of VEGF 165b isoform in the OIR mouse model. We found that both VEGFxxx and VEGFxxxb were present in the mouse retina, among which, VEGF 164 and VEGF 165b appeared to be predominant VEGFxxx and VEGFxxxb isoforms respectively in the mouse retina. We also found that the two family had different expression pattern correlated with neovascularization development and that the relative expression level of VEGF 165b isoform switched during the neovascularization development in the OIR mouse model. In OIR group, the protein level of total VEGF isoforms (a mix of VEGF 164 and VEGF 165b, detected by pan-VEGF antibody) continuously increased and peaked at P17 while VEGF 165b continuously decreased from P9 which was well related with the vessel obliteration and neovascularization development in the mouse model of OIR. The neovascularization development correlates with an increase of total VEGF isoforms and the decrease of VEGF 165b, indicating that there is a pro-angiogenic VEGF shift. Therefore, anti-angiogenic therapy that could alter the ratio of VEGFxxxb/VEGFxxx may be more effective. © 2011 Elsevier Ltd. Source


Shi X.,Peking University | Zhao M.,Peoples Eye Institute | Xie W.-K.,Peoples Eye Institute | Liang J.-H.,Peking University | And 4 more authors.
Chinese Medical Journal | Year: 2013

Background Retinopathy of prematurity (ROP) has become one of the leading causes of visual loss in children. Vascular endothelial growth factor A (VEGF-A) is the principal stimulator of angiogenesis. VEGF was differentially spliced from exon 8 to exons 8a and 8b to form two families: the pro-angiogenic VEGFxxx family and the anti-angiogenic VEGFxxxb family. Previous research has shown variable effeteness of bevacizumab in inhibiting retinal neovascularization in ROP. This study aimed to investigate whether the effectiveness of this inhibition depends on the relative ratio of the two VEGF isoforms. Methods Intravitreal bevacizumab injection (IVB) was performed in the oxygen-induced-retinopathy (OIR) mice on postnatal day 12 (P12) (intravitreal phosphate buffered saline (PBS) injection as control). The Evans blue perfused retina were used to test the retinal neovascularization-leakage (NVL) area and non-perfusion (NP) area. Results The retinal NVL and NP area in the IVB group were significantly smaller than the intravitreal PBS injection group (IVP group). On P17, the protein level of total VEGF isoforms was significantly inhibited compared to IVP group (P<0.05) while VEGF165b isoform was slight reduced (P >0.05). The switch from pro-angiogenic isoforms to anti-angiogenic isoforms after IVB could be found. The relative protein expression of VEGF165b isoform was significantly higher in IVB group than in IVP group (P<0.05) on P17 which was correlated with the reduced ischemia-induced angiogenesis in OIR mice after IVB. Conclusions The anti-angiogenic effectiveness might depend on the relative high expression of VEGF165b after intravitreal bevacizumab injection. Anti-angiogenic therapy is a more effective therapy for ROP. Source


Chen L.,Peking University | Chen L.,Key Laboratory of Cardiovascular Science of the Ministry of Education | Miao Y.,Peking University | Miao Y.,Key Laboratory of Cardiovascular Science of the Ministry of Education | And 18 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012

OBJECTIVE-: The present studies aimed at elucidating the role of prostaglandin E2 receptor subtype 3 (E-prostanoid [EP] 3) in regulating blood pressure. METHODS AND RESULTS-: Mice bearing a genetic disruption of the EP3 gene (EP3) exhibited reduced baseline mean arterial pressure monitored by both tail-cuff and carotid arterial catheterization. The pressor responses induced by EP3 agonists M&B28767 and sulprostone were markedly attenuated in EP3 mice, whereas the reduction of blood pressure induced by prostaglandin E2 was comparable in both genotypes. Vasopressor effect of acute or chronic infusion of angiotensin II (Ang II) was attenuated in EP3 mice. Ang II-induced vasoconstriction in mesenteric arteries decreased in EP3 group. In mesenteric arteries from wild-type mice, Ang II-induced vasoconstriction was inhibited by EP3 selective antagonist DG-041 or L798106. The expression of Arhgef-1 is attenuated in EP3 deficient mesenteric arteries. EP3 antagonist DG-041 diminished Ang II-induced phosphorylation of myosin light chain 20 and myosin phosphatase target subunit 1 in isolated mesenteric arteries. Furthermore, in vascular smooth muscle cells, Ang II-induced intracellular Ca increase was potentiated by EP3 agonist sulprostone but inhibited by DG-041. CONCLUSION-: Activation of the EP3 receptor raises baseline blood pressure and contributes to Ang II-dependent hypertension at least partially via enhancing Ca sensitivity and intracellular calcium concentration in vascular smooth muscle cells. Selective targeting of the EP3 receptor may represent a potential therapeutic target for the treatment of hypertension. © 2012 American Heart Association, Inc. Source


Zhang D.,Peking University | Zhang D.,Key Laboratory of Cardiovascular Science of the Ministry of Education | Yang H.,Peking University | Yang H.,Key Laboratory of Cardiovascular Science of the Ministry of Education | And 17 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2011

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. To date, the molecular mechanisms of DN remain largely unclear. The present study aimed to identify and characterize novel proteins involved in the development of DN by a proteomic approach. Proteomic analysis revealed that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2), the key enzyme in ketogenesis, was increased fourfold in the kidneys of type 2 diabetic db/db mice. Consistently, the activity of HMGCS2 in kidneys and 24-h urinary excretion of the ketone body β-hydroxybutyrate (β-HB) were significantly increased in db/db mice. Immunohistochemistry, immunofluorescence, and real-time PCR studies further demonstrated that HMGCS2 was highly expressed in renal glomeruli of db/db mice, with weak expression in the kidneys of control mice. Because filtered ketone bodies are mainly reabsorbed in the proximal tubules, we used RPTC cells, a rat proximal tubule cell line, to examine the effect of the increased level of ketone bodies. Treating cultured RPTC cells with 1 mM β-HB significantly induced transforming growth factor-β1 expression, with a marked increase in collagen I expression. β-HB treatment also resulted in a marked increase in vimentin protein expression and a significant reduction in E-cadherin protein levels, suggesting an enhanced epithelial-to-mesenchymal transition in RPTCs. Collectively, these findings demonstrate that diabetic kidneys exhibit excess ketogenic activity resulting from increased HMGCS2 expression. Enhanced ketone body production in the diabetic kidney may represent a novel mechanism involved in the pathogenesis of DN. Copyright © 2011 the American Physiological Society. Source

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