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David A Antonetti

Publications and source records attributed to David A Antonetti.

At least 19 recordsLinked to original sources
PubMed2006

A diet-induced mouse model for glutaric aciduria type I.

In the autosomal recessive human disease, glutaric aciduria type I (GA-1), glutaryl-CoA dehydrogenase (GCDH) deficiency disrupts the mitochondrial catabolism of lysine and tryptophan. Affected individuals accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in the serum and often suffer acute striatal injury in childhood. Prior attempts to produce selective striatal vulnerability in an animal model have been unsuccessful. We hypothesized that acute striatal injury may be induced in GCDH-deficient (Gcdh-/-) mice by elevated dietary protein and lysine. Here, we show that high protein diets are lethal to 4-week-old and 8-week-old Gcdh-/- mice within 2-3 days and 7-8 days, respectively. High lysine alone resulted in vasogenic oedema and blood-brain barrier breakdown within the striatum, associated with serum and tissue GA accumulation, neuronal loss, haemorrhage, paralysis, seizures and death in 75% of 4-week-old Gcdh-/- mice after 3-12 days. In contrast, most 8-week-old Gcdh-/- mice survived on high lysine, but developed white matter lesions, reactive astrocytes and neuronal loss after 6 weeks. Thus, the Gcdh-/- mouse exposed to high protein or lysine may be a useful model of human GA-1 including developmentally dependent striatal vulnerability.

Amino Acid Metabolism, Inborn Errors↗
PubMed2006

Pharmacologic manipulation of sphingosine kinase in retinal endothelial cells: implications for angiogenic ocular diseases.

PURPOSE: The increased vascular permeability and pathogenic angiogenesis observed in diabetic retinopathy are induced, at least in part, by local inflammation and vascular endothelial growth factor (VEGF). Therefore, inhibition of signaling from VEGF and tumor necrosis factor-alpha (TNFalpha) is a promising approach to the treatment of this disease, as well as ocular diseases with similar etiologies, including age-related macular degeneration. A growing body of evidence demonstrates that sphingosine kinase (SK) plays an important role in cellular proliferation and angiogenesis. This study was undertaken to examine the effects of SK inhibitors on the responses of retinal endothelial cells (RECs) to VEGF and TNFalpha and their therapeutic efficacy in a diabetic retinopathy model. METHODS: The expression and function of SK in bovine and human RECs were examined by immunoblot analysis. The involvement of SK in mediating responses to VEGF and TNFalpha was examined by using pharmacologic inhibitors of SK in cellular and in vivo assays, including a 3-month streptozotocin-induced diabetic retinopathy model in rats. RESULTS: SK was present and active in human and bovine RECs, and SK activity in these cells was stimulated by VEGF. Inhibitors of SK blocked VEGF-induced production of sphingosine 1-phosphate and markedly attenuated VEGF-induced proliferation and migration of RECs. In addition, SK inhibitors were shown to block TNFalpha-induced expression of adhesion proteins, suppress VEGF-induced vascular leakage in an in vivo mouse model, and reduce retinal vascular leakage in the rat diabetic retinopathy model. CONCLUSIONS: Overall, these studies demonstrate that inhibitors of SK attenuate the effects of proliferative and inflammatory stimuli on RECs both in vitro and in vivo, and so could be significant therapeutics in the treatment of diabetic retinopathy.

Animals↗
PubMed2006

VEGF activation of protein kinase C stimulates occludin phosphorylation and contributes to endothelial permeability.

PURPOSE: VEGF is a potent permeabilizing factor that contributes to the pathogenesis of diabetic retinopathy and brain tumors. VEGF-induced vascular permeability in vivo and in cell culture requires PKC activity, but the mechanism by which PKC regulates barrier properties remains unknown. This study was conducted to examine how VEGF and diabetes alter occludin phosphorylation and endothelial cell permeability. METHODS: Chemical PKC inhibitors and activators were used to treat primary retinal endothelial cells in culture. In vitro kinase assays and Western blot analysis of two-dimensional (2D) and one-dimensional (1D) gel retardation assays were used to analyze occludin phosphorylation. Endothelial cell permeability was determined by measuring the flux of 70-kDa dextran through a cell monolayer in culture. Exogenous expression of a dominant negative PKCbetaII mutant (S217A) was used to assess the PKC dependence of VEGF-induced occludin phosphorylation and endothelial permeability. Occludin phosphorylation was also determined in retinas of streptozotocin-induced diabetic rats. RESULTS: VEGF stimulated the phosphorylation of occludin in primary retinal endothelial cells. Chemical inhibitors of PKC activity blocked the VEGF-induced increase in occludin phosphorylation, as assessed by 2D gel and gel retardation in Western blot analysis, and blocked part of the VEGF-induced monolayer permeability to 70-kDa dextran. Expression of a dominant negative PKCbetaII mutant blocked VEGF-induced occludin phosphorylation and endothelial permeability. Finally, elevated occludin phosphorylation was observed in the retina of diabetic animals. CONCLUSIONS: These results strongly suggest that VEGF-induced endothelial permeability requires PKC-dependent phosphorylation of occludin. Regulation of PKC activity and tight junction protein modifications may have therapeutic implications for treatment of diabetic retinopathy and brain tumors.

Animals↗
PubMed2006

Diabetic retinopathy: seeing beyond glucose-induced microvascular disease.

Diabetic retinopathy remains a frightening prospect to patients and frustrates physicians. Destruction of damaged retina by photocoagulation remains the primary treatment nearly 50 years after its introduction. The diabetes pandemic requires new approaches to understand the pathophysiology and improve the detection, prevention, and treatment of retinopathy. This perspective considers how the unique anatomy and physiology of the retina may predispose it to the metabolic stresses of diabetes. The roles of neural retinal alterations and impaired retinal insulin action in the pathogenesis of early retinopathy and the mechanisms of vision loss are emphasized. Potential means to overcome limitations of current animal models and diagnostic testing are also presented with the goal of accelerating therapies to manage retinopathy in the face of ongoing diabetes.

Diabetic Retinopathy↗
PubMed2006

Diabetes reduces basal retinal insulin receptor signaling: reversal with systemic and local insulin.

Diabetic retinopathy is characterized by early onset of neuronal cell death. We previously showed that insulin mediates a prosurvival pathway in retinal neurons and that normal retina expresses a highly active basal insulin receptor/Akt signaling pathway that is stable throughout feeding and fasting. Using the streptozotocin-induced diabetic rat model, we tested the hypothesis that diabetes diminishes basal retinal insulin receptor signaling concomitantly with increased diabetes-induced retinal apoptosis. The expression, phosphorylation status, and/or kinase activity of the insulin receptor and downstream signaling proteins were investigated in retinas of age-matched control, diabetic, and insulin-treated diabetic rats. Four weeks of diabetes reduced basal insulin receptor kinase, insulin receptor substrate (IRS)-1/2-associated phosphatidylinositol 3-kinase, and Akt kinase activity without altering insulin receptor or IRS-1/2 expression or tyrosine phosphorylation. After 12 weeks of diabetes, constitutive insulin receptor autophosphorylation and IRS-2 expression were reduced, without changes in p42/p44 mitogen-activated protein kinase or IRS-1. Sustained systemic insulin treatment of diabetic rats prevented loss of insulin receptor and Akt kinase activity, and acute intravitreal insulin administration restored insulin receptor kinase activity. Insulin treatment restored insulin receptor-beta autophosphorylation in rat retinas maintained ex vivo, demonstrating functional receptors and suggesting loss of ligand as a cause for reduced retinal insulin receptor/Akt pathway activity. These results demonstrate that diabetes progressively impairs the constitutive retinal insulin receptor signaling pathway through Akt and suggests that loss of this survival pathway may contribute to the initial stages of diabetic retinopathy.

Animals↗
PubMed2005

Shear stress regulates HUVEC hydraulic conductivity by occludin phosphorylation.

Human umbilical vein endothelial cells (HUVECs) display hydraulic conductivity (L(P)) responses to shear stress that differ markedly from the responses of bovine aortic endothelial cells (BAECs). In HUVECs, 5, 10, and 20 dyn cm(-2) steady shear stress transiently increased L(P) with a return to preshear baseline after a 2-h exposure to shear stress. Pure oscillatory shear stress of 0 +/- 20 dyn cm(-2) (mean+/-amplitude) had no effect on L(P), whereas superposition of oscillatory shear stress on steady shear stress suppressed the effect induced by steady shear stress alone. Shear reversal (amplitude greater than mean) was not necessary for the inhibitory influence of oscillatory shear stress. The transient increase of L(P) by steady shear stress was not affected by incubation with BAPTA-AM (10 microM), suggesting calcium independence of the shear response. Decreasing nitric oxide (NO) concentration with L-NMMA (100 microM), a nitric oxide synthase (NOS) inhibitor, did not inhibit the HUVEC L(P) response to shear stress. At the protein level, 10 dyn cm(-2) shear stress did not affect the total content of occludin, but it did elevate the phosphorylation level transiently. The positive correlation between occludin phosphorylation and hydraulic conductivity parallels observations in BAECs and suggests that occludin phosphorylation may be a general mediator of shear-L(P) responses in diverse endothelial cell types.

Animals↗
PubMed2005

Evaluation of the role of P-glycoprotein in the uptake of paroxetine, clozapine, phenytoin and carbamazapine by bovine retinal endothelial cells.

Expression of the drug transport proteins, including P-glycoprotein (Pgp), in the brain vascular endothelium represents a challenge for the effective delivery of drugs for the treatment of several central nervous system (CNS) disorders including depression, schizophrenia and epilepsy. It has been hypothesized that Pgp plays a major role in drug efflux at the blood-brain barrier, and may be an underlying factor in the variable responses of patients to CNS drugs. However, the role of Pgp in the transport of many CNS drugs has not been directly demonstrated. To explore the role of Pgp in drug transport across an endothelial cell barrier derived from the central nervous system, the expression and activity of Pgp in bovine retinal endothelial cells (BRECs) and the effects of representative CNS drugs on Pgp activity were examined. Significant Pgp expression in BRECs was demonstrated by western analyses, and expression was increased by treatment of the cells with hydrocortisone. Intracellular accumulation of the well-characterized Pgp-substrate Taxol was markedly increased by the non-selective transporter inhibitor verapamil and the Pgp-selective antagonist PGP-4008, demonstrating that Pgp is active in these endothelial cells. In contrast, neither verapamil nor PGP-4008 affected the intracellular accumulation of [3H]paroxetine, [14C]phenytoin, [3H]clozapine or [14C]carbamazapine, indicating that these drugs are not substrates for Pgp. Paroxetine, clozapine and phenytoin were shown to be Pgp inhibitors, while carbamazapine did not inhibit Pgp at any concentration tested. These results indicate that Pgp is not likely to modulate patient responses to these drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy.

Loss of blood-retinal barrier (BRB) integrity and vascular permeability characterizes diabetic retinopathy, and new therapies to reverse or prevent vascular permeability are needed to treat this debilitating disease. Glucocorticoids are currently under investigation for use as a local therapeutic treatment for diabetic retinopathy. This review examines the changes that occur to barrier properties in diabetic retinopathy and the potential to use glucocorticoids to restore vascular barrier properties in the retina. Glucocorticoids are useful in preserving the integrity of the blood-brain barrier in the treatment of brain tumors, and these steroids show similar effects on the retinal vasculature suggesting their potential usefulness in treating diabetic retinopathy. Recent progress has been made toward the goal of elucidating the precise mechanism underlying the protective effects of glucocorticoids on the retinal vasculature. Glucocorticoids may act by both suppressing inflammation and by directly affecting the endothelial cells by regulating phosphorylation, organization, and content of tight junction proteins. Further work will advance our understanding of glucocorticoid regulation of barrier properties allowing the ultimate goal of developing a specific and safe therapy to treat or prevent loss of the blood-neural barrier in a number of diseases, including brain tumors and diabetic retinopathy.

Animals↗
PubMed2005

The Ins2Akita mouse as a model of early retinal complications in diabetes.

PURPOSE: This study tested the Ins2(Akita) mouse as an animal model of retinal complications in diabetes. The Ins2(Akita) mutation results in a single amino acid substitution in the insulin 2 gene that causes misfolding of the insulin protein. The mutation arose and is maintained on the C57BL/6J background. Male mice heterozygous for this mutation have progressive loss of beta-cell function, decreased pancreatic beta-cell density, and significant hyperglycemia, as early as 4 weeks of age. METHODS: Heterozygous Ins2(Akita) mice were bred to C57BL/6J mice, and male offspring were monitored for hyperglycemia, beginning at 4.5 weeks of age. After 4 to 36 weeks of hyperglycemia, the retinas were analyzed for vascular permeability, vascular lesions, leukostasis, morphologic changes of micro- and macroglia, apoptosis, retinal degeneration, and insulin receptor kinase activity. RESULTS: The mean blood glucose of Ins2(Akita) mice was significantly elevated, whereas the body weight at death was reduced compared with that of control animals. Compared with sibling control mice, the Ins2(Akita) mice had increased retinal vascular permeability after 12 weeks of hyperglycemia (P < 0.005), a modest increase in acellular capillaries after 36 weeks of hyperglycemia (P < 0.0008), and alterations in the morphology of astrocytes and microglia, but no changes in expression of Muller cell glial fibrillary acidic protein. Increased apoptosis was identified by immunoreactivity for active caspase-3 after 4 weeks of hyperglycemia (P < 0.01). After 22 weeks of hyperglycemia, there was a 16.7% central and 27% peripheral reduction in the thickness of the inner plexiform layer, a 15.6% peripheral reduction in the thickness of the inner nuclear layer (P < 0.001), and a 23.4% reduction in the number of cell bodies in the retinal ganglion cell layer (P < 0.005). In vitro insulin receptor kinase activity was reduced (P < 0.05) after 12 weeks of hyperglycemia. CONCLUSIONS: The retinas of heterozygous male Ins2(Akita) mice exhibit vascular, neural, and glial abnormalities generally consistent with clinical observations and other animal models of diabetes. In light of the relatively early, spontaneous onset of the disease and the popularity of the C57BL/6J inbred strain as a background for the generation and study of other genetic alterations, combining the Ins2(Akita) mutation with other engineered mutations will be of great use for studying the molecular basis of retinal complications of diabetes.

Animals↗
PubMed2004

Alterations in expression of angiopoietins and the Tie-2 receptor in the retina of streptozotocin induced diabetic rats.

PURPOSE: The angiopoietin (Ang)/Tie-2 system may play a role in vascular integrity and angiogenesis. In this study, we investigated alterations of the gene expression of Ang-1 and Ang-2 in the retinas of streptozotocin (STZ) induced diabetic rats. METHODS: In situ hybridization, reverse transcriptase polymerase chain reaction (RT-PCR) and western blot analyses were performed to determine the mRNA and protein content for Ang-1 and Ang-2 and the Tie2 receptor in the retinas of STZ diabetic and age matched control rats. RESULTS: Using in situ hybridization analysis, Ang-1, Ang-2, and Tie2 mRNA expression was observed in the ganglion cell layer (GCL) and the inner nuclear layer (INL). While Ang-2 mRNA expression did not changed after 2 weeks, 1 month, or 3 months of STZ induced diabetes, it was increased in the GCL and slightly elevated in the INL after 6 months of diabetes. In contrast, Ang-1 and Tie2 mRNA expression was stable at every timepoint during 6 months of STZ induced diabetes. RT-PCR and western blot analyses confirmed the increase of Ang-2 expression after 6 months of diabetes. Furthermore, double staining of alpha-smooth muscle actin (alphaSMA) and Ang-2 mRNA demonstrated that the SMA positive cells surrounding Ang-2-expressing cells were decreased in the GCL. CONCLUSIONS: Diabetes increases Ang-2 expression in the GCL accompanied by a reduction of alphaSMA positive perivascular cells. These changes may suggest a role for Ang-2 in the mechanism of pericyte loss in diabetic retinopathy.

Angiopoietin-1↗
PubMed2004

Regulation of tight junctions and loss of barrier function in pathophysiology.

The mechanism by which epithelial and endothelial cells interact to form polarized tissue is of fundamental importance to multicellular organisms. Dysregulation of these barriers occurs in a variety of diseases, destroying the normal cellular environments and leading to organ failure. Increased levels of growth factors are a common characteristic of diseases exhibiting tissue permeability, suggesting that growth factors play a direct role in elevating permeability. Of particular concern for this laboratory, increased expression of vascular endothelial growth factor may enhance vascular permeability in diabetic retinopathy, leading to vision impairment and blindness. However, the mechanism by which growth factors increase permeability is unclear. Polarized cells form strong barriers through the development of tight junctions, which are specialized regions of the junctional complex. Tight junctions are composed of three types of transmembrane proteins, a number of peripheral membrane structural proteins, and are associated with a variety of regulatory proteins. Recent data suggest that growth factor-stimulated alterations in tight junctions contribute to permeability in a variety of disease states. The goal of this review was to elucidate potential mechanisms by which elevated growth factors elicit deregulated paracellular permeability via altered regulation of tight junctions, with particular emphasis on the tight junction proteins occludin and ZO-1, protein kinase C signaling, and endocytosis of junctional proteins. Understanding the molecular mechanisms underlying growth factor-mediated regulation of tight junctions will facilitate the development of novel treatments for diseases such as brain tumors, diabetic retinopathy and other diseases with compromised tight junction barriers.

Cell Membrane Permeability↗
PubMed2004

VEGF increases paracellular transport without altering the solvent-drag reflection coefficient.

Vascular endothelial growth factor (VEGF) increases microvascular permeability and has been implicated in the development of numerous pathologies including diabetic retinopathy (DR), hypoxia/ischemia, and tumor biology. The transport pathways by which water and solutes cross the endothelium in response to VEGF, however, are not completely understood. We measured, in real time, bovine retinal endothelial cell (BREC) hydraulic conductivity (Lp), 70 kDa dextran permeability (Pe), and the solvent-drag reflection coefficient (sigma) before and after addition of 50 ng/ml VEGF. The diffusional permeability coefficient for dextran (Pd) was measured before pressure gradient application. The sudden application of a 10-cm H2O hydrostatic pressure gradient induced water and solute fluxes that decayed to steady-state values after approximately 2 h. Subsequently, the addition of VEGF significantly increased Lp and Pe by 4.3-fold +/- 0.7-fold and 3.0-fold +/- 0.3-fold, respectively, after 110 min; however, the reflection coefficient remained approximately constant throughout the experiment (approximately 0.8). These observations suggest that water and dextran utilize common paracellular channels across BREC monolayers. Furthermore, the addition of VEGF increases the number or availability of channels but does not alter the selectivity of the monolayer to 70 kDa dextran.

Animals↗
PubMed2003

Insulin promotes rat retinal neuronal cell survival in a p70S6K-dependent manner.

The purpose of this study was to examine the role of the ribosomal protein S6 protein kinase (p70S6K), a protein synthesis regulator, in promoting retinal neuronal cell survival. Differentiated R28 rat retinal neuronal cells were used as an experimental model. Cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% newborn calf serum, and during the period of experimentation were exposed either to the absence or presence of 10 nm insulin. Insulin treatment induced p70S6K, mTOR, and Akt phosphorylation, effects that were completely prevented by the PI3K inhibitor, LY294002. Insulin-induced phosphorylation of p70S6K and mTOR was prevented by the mTOR inhibitor, rapamycin. Apoptosis, induced by serum deprivation and evaluated by Hoechst staining, was inhibited by insulin treatment in R28 cells, but not in L6 muscle cells. This effect of insulin was also largely prevented by rapamycin. Inhibition of p70S6K activity by exogenous expression of a dominant negative mutant of p70S6K prevented insulin-induced cell survival, whereas, overexpression of wild type p70S6K or expression of a rapamycin resistant form of the kinase enhanced the effect of insulin on survival. Enhanced cell survival under the latter condition was accompanied by increased p70S6K activity and phosphorylation. Rapamycin did not inhibit insulin induced p70S6K phosphorylation and activity in cells transfected with the rapamycin-resistant mutant. Together, these results suggest that p70S6K plays a key role in insulin stimulated retinal neuronal cell survival.

Animals↗
PubMed2003

A transmural pressure gradient induces mechanical and biological adaptive responses in endothelial cells.

A sudden increase in the transmural pressure gradient across endothelial monolayers reduces hydraulic conductivity (L(p)), a phenomenon known as the sealing effect. To further characterize this endothelial adaptive response, we measured bovine aortic endothelial cell (BAEC) permeability to albumin and 70-kDa dextran, L(p), and the solvent-drag reflection coefficients (sigma) during the sealing process. The diffusional permeability coefficients for albumin (1.33 +/- 0.18 x 10(-6) cm/s) and dextran (0.60 +/- 0.16 x 10(-6) cm/s) were measured before pressure application. The effective permeabilities (measured when solvent drag contributes to solute transport) of albumin and dextran (P(ealb) and P(edex)) were measured after the application of a 10 cmH(2)O pressure gradient; during the first 2 h of pressure application, P(ealb), P(edex), and L(p) were significantly reduced by 2.0 +/- 0.3-, 2.1 +/- 0.3-, and 3.7 +/- 0.3-fold, respectively. Immunostaining of the tight junction (TJ) protein zonula occludens-1 (ZO-1) was significantly increased at cell-cell contacts after the application of transmural pressure. Cytochalasin D treatment significantly elevated transport but did not inhibit the adaptive response, whereas colchicine treatment had no effect on diffusive permeability but inhibited the adaptive response. Neither cytoskeletal inhibitor altered sigma despite significantly elevating both L(p) and effective permeability. Our data suggest that BAECs actively adapt to elevated transmural pressure by mobilizing ZO-1 to intercellular junctions via microtubules. A mechanical (passive) component of the sealing effect appears to reduce the size of a small pore system that allows the transport of water but not dextran or albumin. Furthermore, the structures of the TJ determine transport rates but do not define the selectivity of the monolayer to solutes (sigma).

Animals↗
PubMed2003

Characterization of insulin signaling in rat retina in vivo and ex vivo.

Insulin receptor (IR) signaling cascades have been studied in many tissues, but retinal insulin action has received little attention. Retinal IR signaling and activity were investigated in vivo in rats that were freely fed, fasted, or injected with insulin by phosphotyrosine immunoblotting and by measuring kinase activity. A retina explant system was utilized to investigate the IR signaling cascade, and immunohistochemistry was used to determine which retinal cell layers respond to insulin. Basal IR activity in the retina was equivalent to that in brain and significantly greater than that of liver, and it remained constant between freely fed and fasted rats. Furthermore, IR signaling increased in the retina after portal vein administration of supraphysiological doses of insulin. Ex vivo retinas responded to 10 nM insulin with IR beta-subunit (IRbeta) and IR substrate-2 (IRS-2) tyrosine phosphorylation and AktSer473 phosphorylation. The retina expresses mRNA for all three Akt isoforms as determined by in situ hybridization, and insulin specifically increases Akt-1 kinase activity. Phospho-AktSer473 immunoreactivity increases in retinal nuclear cell layers with insulin treatment. These results demonstrate that the retinal IR signaling cascade to Akt-1 possesses constitutive activity, and that exogenous insulin further stimulates this prosurvival pathway. These findings may have implications in understanding normal and dysfunctional retinal physiology.

Animals↗
PubMed2003

Mapping the blood vessels with paracellular permeability in the retinas of diabetic rats.

PURPOSE: Diabetic retinopathy increases the permeability of the blood-retinal barrier, but the specific vessels that become permeable have not been identified. Both transcellular and paracellular pathways of vascular solute flux have been proposed. This study was conducted to test the hypothesis that paracellular flux contributes to increased retinal vascular permeability after VEGF treatment or diabetes, and to map the types of vessels that became permeable. METHODS: Regions of paracellular flux were identified by perfusion with fluorescent concanavalin A (ConA). Rats were injected intravitreally with VEGF or made diabetic with streptozotocin (STZ). After specified times, the rats were perfused with fixative followed by ConA, which binds to the basement membrane but not the luminal surface of endothelial cells. With this approach, ConA labels only blood vessels with paracellular permeability. Retinas were also labeled by immunofluorescence for the tight junction proteins occludin and claudin-5 and examined by confocal microscopy. RESULTS: ConA labeling increased in the superficial arterioles and postcapillary venules, 2 weeks after the onset of diabetes. After 1 month, ConA labeling dramatically increased and extended to the capillaries of the outer plexiform layer. There was an inverse relationship between occludin immunoreactivity and ConA binding, but no change in claudin-5 immunoreactivity was detected. Injection of VEGF gave similar results. CONCLUSIONS: Diabetes and VEGF increase paracellular vascular permeability in the retina, associated with redistribution of occludin. This permeability begins in the superficial arterioles and postcapillary venules and progresses to the capillary bed.

Animals↗