Enhanced permeability responses to inflammation in streptozotocin-induced diabetic rat venules: Rho-mediated alterations of actin cytoskeleton and VE-cadherin

Dong Yuan, Sulei Xu, Pingnian He

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11 Citations (Scopus)

Abstract

Diabetes is a progressive disease that often leads to microvascular complications. This study investigates the impact of diabetes on microvessel permeability under basal and inflammatory conditions. Streptozotocin-induced diabetic rats were used to mimic type 1 diabetes. Parallel experiments were conducted in intact mesenteric venules in normal rats and diabetic rats experiencing hyperglycemia for 2-3 wk. Microvessel permeability was determined by measuring hydraulic conductivity (Lp). The correlated changes in endothelial intracellular Ca2+ concentration ([Ca2+]i), adherens junctions, and cytoskeleton F-actin were examined with fluorescence imaging. Diabetic vessels showed moderately increased basal Lp, but upon platelet-activating factor (PAF) exposure, these vessels showed an ~10-fold higher Lp increase than the normal vessels. Concomitantly, we observed higher increases in endothelial [Ca2+]i, enhanced stress fiber formation, vascular endothelial-cadherin separation, and larger gap formation between endothelial cells than those occurring in normal vessels. PAF receptor staining showed no significant difference between normal and diabetic vessels. The application of Rho kinase inhibitor Y27632 did not affect PAF-induced increases in endothelial [Ca2+]i but significantly reduced PAF-induced Lp increases by 90% in diabetic vessels. The application of both Y27632 and nitric oxide (NO) synthase inhibitor attenuated PAF-induced Lp increases more than using one inhibitor alone. Our studies indicate that diabetic conditions prime endothelial cells into a phenotype with increased susceptibility to inflammation without altering receptor expression and that the increased Rho activation and NO production play important roles in exaggerated permeability increases when diabetic vessels were exposed to inflammatory mediators, which may account for the exacerbated vascular dysfunction when diabetic patients are exposed to additional inflammation.

Original languageEnglish (US)
Pages (from-to)H44-H53
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume307
Issue number1
DOIs
StatePublished - Jul 1 2014

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Venules
Platelet Activating Factor
Streptozocin
Actin Cytoskeleton
Permeability
Inflammation
Microvessels
Endothelial Cells
Adherens Junctions
rho-Associated Kinases
Stress Fibers
Optical Imaging
Cytoskeleton
Type 1 Diabetes Mellitus
Nitric Oxide Synthase
Hyperglycemia
Blood Vessels
Actins
Nitric Oxide
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

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title = "Enhanced permeability responses to inflammation in streptozotocin-induced diabetic rat venules: Rho-mediated alterations of actin cytoskeleton and VE-cadherin",
abstract = "Diabetes is a progressive disease that often leads to microvascular complications. This study investigates the impact of diabetes on microvessel permeability under basal and inflammatory conditions. Streptozotocin-induced diabetic rats were used to mimic type 1 diabetes. Parallel experiments were conducted in intact mesenteric venules in normal rats and diabetic rats experiencing hyperglycemia for 2-3 wk. Microvessel permeability was determined by measuring hydraulic conductivity (Lp). The correlated changes in endothelial intracellular Ca2+ concentration ([Ca2+]i), adherens junctions, and cytoskeleton F-actin were examined with fluorescence imaging. Diabetic vessels showed moderately increased basal Lp, but upon platelet-activating factor (PAF) exposure, these vessels showed an ~10-fold higher Lp increase than the normal vessels. Concomitantly, we observed higher increases in endothelial [Ca2+]i, enhanced stress fiber formation, vascular endothelial-cadherin separation, and larger gap formation between endothelial cells than those occurring in normal vessels. PAF receptor staining showed no significant difference between normal and diabetic vessels. The application of Rho kinase inhibitor Y27632 did not affect PAF-induced increases in endothelial [Ca2+]i but significantly reduced PAF-induced Lp increases by 90{\%} in diabetic vessels. The application of both Y27632 and nitric oxide (NO) synthase inhibitor attenuated PAF-induced Lp increases more than using one inhibitor alone. Our studies indicate that diabetic conditions prime endothelial cells into a phenotype with increased susceptibility to inflammation without altering receptor expression and that the increased Rho activation and NO production play important roles in exaggerated permeability increases when diabetic vessels were exposed to inflammatory mediators, which may account for the exacerbated vascular dysfunction when diabetic patients are exposed to additional inflammation.",
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