ABSTRACT
Hyperglycemia causes micro- and macrovascular complications in diabetic patients. Elevated glucose concentrations lead to increased formation of the highly reactive dicarbonyl methylglyoxal (MG), yet the early consequences of MG for development of vascular complications in vivo are poorly understood. In this study, zebrafish were used as a model organism to analyze early vascular effects and mechanisms of MG in vivo. High tissue glucose increased MG concentrations in tg(fli:EGFP) zebrafish embryos and rapidly induced several additional malformed and uncoordinated blood vessel structures that originated out of existing intersomitic blood vessels (ISVs). However, larger blood vessels, including the dorsal aorta and common cardinal vein, were not affected. Expression silencing of MG-degrading enzyme glyoxalase (glo) 1 elevated MG concentrations and induced a similar vascular hyperbranching phenotype in zebrafish. MG enhanced phosphorylation of vascular endothelial growth factor (VEGF) receptor 2 and its downstream target Akt/protein kinase B (PKB). Pharmacological inhibitors for VEGF receptor 2 and Akt/PKB as well as MG scavenger aminoguanidine and glo1 activation prevented MG-induced hyperbranching of ISVs. Taken together, MG acts on smaller blood vessels in zebrafish via the VEGF receptor signaling cascade, thereby describing a new mechanism that can explain vascular complications under hyperglycemia and elevated MG concentrations.
Subject(s)
Blood Vessels/metabolism , Glucose/metabolism , Pyruvaldehyde/metabolism , Signal Transduction/physiology , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Zebrafish Proteins/metabolism , Animals , Animals, Genetically Modified , Blood Vessels/abnormalities , Female , Gene Expression Regulation, Developmental , Green Fluorescent Proteins/genetics , Male , Neovascularization, Physiologic/physiology , Proto-Oncogene Proteins c-akt/metabolism , Vascular Endothelial Growth Factor Receptor-2/genetics , Zebrafish/embryology , Zebrafish/genetics , Zebrafish Proteins/geneticsABSTRACT
OBJECTIVE: The objective of the study was to determine incontinence pessaries' mechanism of action by measuring changes on urodynamic studies (UDS) and dynamic magnetic resonance imaging (MRI) with and without pessaries in place. STUDY DESIGN: Women with stress incontinence had UDS and MRI performed with and without incontinence dish pessaries. RESULTS: Fifteen women were evaluated. Pessary insertion resulted in increased urethral resistance; detrusor pressures increased (33-45 cm H(2)O) and maximal flow rates decreased (30 to 19 mL/second). With Valsalva on MRI, pessaries were associated with decreased posterior urethrovesical angles (175-130 degrees), bladder neck elevation (0.3 below to 0 .8 cm above the pubococcygeal line) and increased urethral lengths (2.4 to 2.97 cm). Bladder neck funneling with cough occurred in 14 patients without pessaries and 3 with pessaries. CONCLUSION: On UDS and MRI following pessary placement, continence restoration was associated with decreased posterior urethrovesical angles, bladder neck descent and funneling, and increased urethral lengths and resistance to urine flow.
