Vascular Stability Research Articles

Maternal vascular endothelial growth factor receptor and interleukin levels in pregnant women with twin-twin transfusion syndrome.

Twin-twin transfusion syndrome (TTTS) is an unusual and serious condition that occurs in twin pregnancies when identical twins share a placenta but develop discordant amniotic fluid volumes. TTTS is associated with an increased risk of fetal death and birth defects if untreated. This study investigated the soluble levels of biomarkers including growth factors and interleukins in pregnant women with and without TTTS during pregnancy. We quantified plasma levels of VEGF-R1, VEGF-R2, IL-1β, IL-6 and IL-8 in twin pregnant women with (n=53) and without TTTS (n=72) and in women with single pregnancy (n=30) by ELISA and analyzed the association of maternal circulating biomarker levels with TTTS. Our results showed that maternal VEGF-R1 levels were significantly higher in twins compared to single pregnancy (P<0.05) and were decreased in the second trimester compared to the first trimester (P = 0.065, 0.019 and 0.072 for twins with and without TTTS and single pregnancy, respectively). VEGF-R2 levels had a trend to be lower in twins compared to single pregnancy. In addition, soluble VEGF-R1 and VEGF-R2 levels were significantly decreased while IL-6 levels were increased after surgical treatment with laser in twin pregnant women with TTTS (P = 0.016, 0.041 and 0.04, respectively). These results suggest that IL-6, VEGF-R1 and VEGF-R2 are involved in vascular regulation and stabilization in twin pregnancies and may contribute to the pathogenesis of TTTS and thus play a prognostic role in the surgical treatment of TTTS.

Targeting the Ang2/Tie2 Axis with Tanshinone IIA Elicits Vascular Normalization in Ischemic Injury and Colon Cancer.

Pathological angiogenesis, as exhibited by aberrant vascular structure and function, has been well deemed to be a hallmark of cancer and various ischemic diseases. Therefore, strategies to normalize vasculature are of potential therapeutic interest in these diseases. Recently, identifying bioactive compounds from medicinal plant extracts to reverse abnormal vasculature has been gaining increasing attention. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza, has been shown to play significant roles in improving blood circulation and delaying tumor progression. However, the underlying mechanisms responsible for the therapeutic effects of Tan IIA are not fully understood. Herein, we established animal models of HT-29 human colon cancer xenograft and hind limb ischemia to investigate the role of Tan IIA in regulating abnormal vasculature. Interestingly, our results demonstrated that Tan IIA could significantly promote the blood flow, alleviate the hypoxia, improve the muscle quality, and ameliorate the pathological damage after ischemic insult. Meanwhile, we also revealed that Tan IIA promoted the integrity of vascular structure, reduced vascular leakage, and attenuated the hypoxia in HT-29 tumors. Moreover, the circulating angiopoietin 2 (Ang2), which is extremely high in these two pathological states, was substantially depleted in the presence of Tan IIA. Also, the activation of Tie2 was potentiated by Tan IIA, resulting in decreased vascular permeability and elevated vascular integrity. Mechanistically, we uncovered that Tan IIA maintained vascular stability by targeting the Ang2-Tie2-AKT-MLCK cascade. Collectively, our data suggest that Tan IIA normalizes vessels in tumors and ischemic injury via regulating the Ang2/Tie2 signaling pathway.

Process of extraction and isolation of canthaxanthin from saline bacteria biomass &lt;i&gt;Paracoccus carotinifaciens&lt;/i&gt; VTP20181 isolated in Vietnam

Canthaxanthin is a natural carotenoid, which can be biosynthesized from several different bacterial strains and exhibits a wide range of biological benefits such as antioxidant, immune booster, and vascular stabilization. Canthaxanthin is widely used in the food and pharmaceutical industries as a natural colourant, and its production from natural sources has been the topic of growing interest. In this study, we established the process of extracting, enriching and isolating canthaxanthin from the post-fermentation biomass of the saline bacteria Paracoccus carotinifaciens VTP20181 isolated in Vietnam at laboratory scale. This process consists of 5 steps: Dry biomass generation, dry biomass extraction, removal of saturated fat, fast column chromatography and slow column chromatography, canthaxanthin purification. Canthaxanthin compound is obtained with 98% purity. Canthaxanthin extraction and purification efficiency of the whole process reached 55.5%.

Angiopoietin-2 Promotes Inflammatory Activation in Monocytes of Systemic Sclerosis Patients

Angiopoietin-2 (Ang-2), a ligand of the tyrosine kinase receptor Tie2, is essential for vascular development and blood vessel stability and is also involved in monocyte activation. Here, we examined the role of Ang-2 on monocyte activation in patients with systemic sclerosis (SSc). Ang-2 levels were measured in serum and skin of healthy controls (HCs) and SSc patients by ELISA and array profiling, respectively. mRNA expression of ANG2 was analyzed in monocytes, dermal fibroblasts, and human pulmonary arterial endothelial cells (HPAECs) by quantitative PCR. Monocytes were stimulated with Ang-2, or with serum from SSc patients in the presence of a Tie2 inhibitor or an anti-Ang2 neutralizing antibody. Interleukin (IL)-6 and IL-8 production was analyzed by ELISA. Ang-2 levels were elevated in the serum and skin of SSc patients compared to HCs. Importantly, serum Ang-2 levels correlated with clinical disease parameters, such as skin involvement. Lipopolysaccharide (LPS) LPS, R848, and interferon alpha2a (IFN-α) stimulation up-regulated the mRNA expression of ANG2 in monocytes, dermal fibroblasts, and HPAECs. Finally, Ang-2 induced the production of IL-6 and IL-8 in monocytes of SSc patients, while the inhibition of Tie2 or the neutralization of Ang-2 reduced the production of both cytokines in HC monocytes stimulated with the serum of SSc patients. Therefore, Ang-2 induces inflammatory activation of SSc monocytes and neutralization of Ang-2 might be a promising therapeutic target in the treatment of SSc.

The Effects and Underlying Mechanisms of Cell Therapy on Blood-Brain Barrier Integrity After Ischemic Stroke.

Ischemic stroke is one of the main causes of mortality and disability worldwide. However, efficient therapeutic strategies are still lacking. Stem/progenitor cell-based therapy, with its vigorous advantages, has emerged as a promising tool for the treatment of ischemic stroke. The mechanisms involve new neural cells and neuronal circuitry formation, antioxidation, inflammation alleviation, angiogenesis, and neurogenesis promotion. In the past decades, in-depth studies have suggested that cell therapy could promote vascular stabilization and decrease blood-brain barrier (BBB) leakage after ischemic stroke. However, the effects and underlying mechanisms on BBB integrity induced by the engrafted cells in ischemic stroke have not been reviewed yet. Herein, we will update the progress in research on the effects of cell therapy on BBB integrity after ischemic stroke and review the underlying mechanisms. First, we will present an overview of BBB dysfunction under the ischemic condition and cells engraftment for ischemic treatment. Then, we will summarize and discuss the current knowledge about the effects and underlying mechanisms of cell therapy on BBB integrity after ischemic stroke. In particular, we will review the most recent studies in regard to the relationship between cell therapy and BBB in tissue plasminogen activator (t-PA)-mediated therapy and diabetic stroke.

Abstract 15245: Cd34+ Progenitor Cells in the Progression of Cardiac Allograft Vasculopathy

Introduction: CD34+ progenitor cells play a role in vascular repair and plaque stability. However, their role in cardiac allograft vasculopathy (CAV), vessel remodeling, and changes in plaque morphology is incompletely understood. Hypothesis: We hypothesized that decreased levels of baseline CD34+ progenitor cells would be associated with Intravascular Ultrasound (IVUS)-defined vulnerable plaque characteristics and CAV progression. Methods: In heart transplant patients undergoing annual IVUS, CD34+ cells were counted in peripheral blood using flow cytometry, on the same day as baseline IVUS. Gray-scale and virtual-histology IVUS were used to evaluate vessel size, plaque burden, and plaque composition (fibrous, fibrofatty, necrotic core, calcific). Positive remodeling was defined as expansion of external elastic membrane area on follow-up. Patients were divided into two groups by the median of the change (Δ) in necrotic core volume over the subsequent 3 years. Results: A total of 55 patients (mean age 52±15 years, 65% males) were included. Median time after transplant was 4.2 years at baseline. Average vessel area at baseline and three years were 15.8±4.6 and 15.3±5.4 mm, respectively (p=0.32). Twenty-four patients (44%) who showed positive remodeling at follow-up, compared to those who did not, had lower levels of baseline CD34+ progenitor cells (absolute count per 100,000 counts, 980 [690, 1460]) vs. 665 [438, 1015], p=0.02) (Fig. 1A). Patients with greater than median (&gt;1.96 mm3) Δnecrotic core volume, as compared to those with below median Δ, also had lower baseline CD34+ cells (705 [483, 998] vs. 1180 [660, 1620] per 100,000 counts, p=0.04) (Fig. 1B). Conclusions: Lower levels of CD34+ progenitor cells are associated with long-term positive coronary vascular remodeling and increased plaque necrotic core volume in patients who underwent allograft heart transplant. This study supports the notion that circulating CD34+ progenitor cells play a role in CAV.

Dual function of perivascular fibroblasts in vascular stabilization in zebrafish.

Blood vessels are vital to sustain life in all vertebrates. While it is known that mural cells (pericytes and smooth muscle cells) regulate vascular integrity, the contribution of other cell types to vascular stabilization has been largely unexplored. Using zebrafish, we identified sclerotome-derived perivascular fibroblasts as a novel population of blood vessel associated cells. In contrast to pericytes, perivascular fibroblasts emerge early during development, express the extracellular matrix (ECM) genes col1a2 and col5a1, and display distinct morphology and distribution. Time-lapse imaging reveals that perivascular fibroblasts serve as pericyte precursors. Genetic ablation of perivascular fibroblasts markedly reduces collagen deposition around endothelial cells, resulting in dysmorphic blood vessels with variable diameters. Strikingly, col5a1 mutants show spontaneous hemorrhage, and the penetrance of the phenotype is strongly enhanced by the additional loss of col1a2. Together, our work reveals dual roles of perivascular fibroblasts in vascular stabilization where they establish the ECM around nascent vessels and function as pericyte progenitors.

New soluble angiopoietin analog of Hepta-ANG1 prevents pathological vascular leakage.

Vascular leak is a key driver of organ injury in diseases, and strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets. Activation of the angiopoietin-1 (ANG1)-Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence. Here we describe the design and construction of a new soluble ANG1 mimetic that is a potent activator of endothelial Tie2 in vitro and in vivo. Using a chimeric fusion strategy, we replaced the extracellular matrix (ECM) binding and oligomerization domain of ANG1 with a heptameric scaffold derived from the C-terminus of serum complement protein C4-binding protein α. We refer to this new fusion protein biologic as Hepta-ANG1, which forms a stable heptamer and induces Tie2 phosphorylation in cultured cells, and in the lung following intravenous injection of mice. Injection of Hepta-ANG1 ameliorates vascular endothelial growth factor- and lipopolysaccharide-induced vascular leakage, in keeping with the known functions of Angpt1-Tie2 in maintaining quiescent vascular stability. The new Hepta-ANG1 fusion is easy to produce and displays remarkable stability with high multimericity that can potently activate Tie2. It could be a new candidate ANG1 mimetic therapy for treatments of inflammatory vascular leak, such as acute respiratory distress syndrome and sepsis.

Wnt Pathway: An Emerging Player in Vascular and Traumatic Mediated Brain Injuries.

The Wnt pathway, which comprises the canonical and non-canonical pathways, is an evolutionarily conserved mechanism that regulates crucial biological aspects throughout the development and adulthood. Emergence and patterning of the nervous and vascular systems are intimately coordinated, a process in which Wnt pathway plays particularly important roles. In the brain, Wnt ligands activate a cell-specific surface receptor complex to induce intracellular signaling cascades regulating neurogenesis, synaptogenesis, neuronal plasticity, synaptic plasticity, angiogenesis, vascular stabilization, and inflammation. The Wnt pathway is tightly regulated in the adult brain to maintain neurovascular functions. Historically, research in neuroscience has emphasized essentially on investigating the pathway in neurodegenerative disorders. Nonetheless, emerging findings have demonstrated that the pathway is deregulated in vascular- and traumatic-mediated brain injuries. These findings are suggesting that the pathway constitutes a promising target for the development of novel therapeutic protective and restorative interventions. Yet, targeting a complex multifunctional signal transduction pathway remains a major challenge. The review aims to summarize the current knowledge regarding the implication of Wnt pathway in the pathobiology of ischemic and hemorrhagic stroke, as well as traumatic brain injury (TBI). Furthermore, the review will present the strategies used so far to manipulate the pathway for therapeutic purposes as to highlight potential future directions.

Intra-Tumoral Angiogenesis Is Associated with Inflammation, Immune Reaction and Metastatic Recurrence in Breast Cancer.

Angiogenesis is one of the hallmarks of cancer. We hypothesized that intra-tumoral angiogenesis correlates with inflammation and metastasis in breast cancer patients. To test this hypothesis, we generated an angiogenesis pathway score using gene set variation analysis and analyzed the tumor transcriptome of 3999 breast cancer patients from The Cancer Genome Atlas Breast Cancer (TCGA-BRCA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE20194, GSE25066, GSE32646, and GSE2034 cohorts. We found that the score correlated with expression of various angiogenesis-, vascular stability-, and sphingosine-1-phosphate (S1P)-related genes. Surprisingly, the angiogenesis score was not associated with breast cancer subtype, Nottingham pathological grade, clinical stage, response to neoadjuvant chemotherapy, or patient survival. However, a high score was associated with a low fraction of both favorable and unfavorable immune cell infiltrations except for dendritic cell and M2 macrophage, and with Leukocyte Fraction, Tumor Infiltrating Lymphocyte Regional Fraction and Lymphocyte Infiltration Signature scores. High-score tumors had significant enrichment for unfavorable inflammation-related gene sets (interleukin (IL)6, and tumor necrosis factor (TNF)α- and TGFβ-signaling), as well as metastasis-related gene sets (epithelial mesenchymal transition, and Hedgehog-, Notch-, and WNT-signaling). High score was significantly associated with metastatic recurrence particularly to brain and bone. In conclusion, using the angiogenesis pathway score, we found that intra-tumoral angiogenesis is associated with immune reaction, inflammation and metastasis-related pathways, and metastatic recurrence in breast cancer.

New Insights Into Blood-Brain Barrier Maintenance: The Homeostatic Role of β-Amyloid Precursor Protein in Cerebral Vasculature.

Cerebrovascular homeostasis is maintained by the blood-brain barrier (BBB), a highly selective structure that separates the peripheral blood circulation from the brain and protects the central nervous system (CNS). Dysregulation of BBB function is the precursor of several neurodegenerative diseases including Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), both related to β-amyloid (Aβ) accumulation and deposition. The origin of BBB dysfunction before and/or during CAA and AD onset is not known. Several studies raise the possibility that vascular dysfunction could be an early step in these diseases and could even precede significant Aβ deposition. Though accumulation of neuron-derived Aβ peptides is considered the primary influence driving AD and CAA pathogenesis, recent studies highlighted the importance of the physiological role of the β-amyloid precursor protein (APP) in endothelial cell homeostasis, suggesting a potential role of this protein in maintaining vascular stability. In this review, we will discuss the physiological function of APP and its cleavage products in the vascular endothelium. We further suggest how loss of APP homeostatic regulation in the brain vasculature could lead toward pathological outcomes in neurodegenerative disorders.

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Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling.

Persistent inflammation is a complication associated with many ocular diseases. Changes in ocular vessels can amplify disease responses and contribute to vision loss by influencing the delivery of leukocytes to the eye, vascular leakage, and perfusion. Here, we report the anti-inflammatory activity for AXT107, a non-RGD, 20-mer αvβ3 and α5β1 integrin-binding peptide that blocks vascular endothelial growth factor (VEGF)-signaling and activates tyrosine kinase with immunoglobulin and EGF-like domains 2 (Tie2) using the normally inhibitory ligand angiopoietin 2 (Ang2). Tumor necrosis factor α (TNFα), a central inflammation mediator, induces Ang2 release from endothelial cells to enhance its stimulation of inflammation and vascular leakage. AXT107 resolves TNFα-induced vascular inflammation in endothelial cells by converting the endogenously released Ang2 into an agonist of Tie2 signaling, thereby disrupting both the synergism between TNFα and Ang2 while also preventing inhibitor of nuclear factor-κB α (IκBα) degradation directly through Tie2 signaling. This recovery of IκBα prevents nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear localization, thereby blocking NF-κB-induced inflammatory responses, including the production of VCAM-1 and ICAM-1, leukostasis, and vascular leakage in cell and mouse models. AXT107 also decreased the levels of pro-inflammatory TNF receptor 1 (TNFR1) without affecting levels of the more protective TNFR2. These data suggest that AXT107 may provide multiple benefits in the treatment of retinal/choroidal and other vascular diseases by suppressing inflammation and promoting vascular stabilization.

The effects of human prothrombin complex concentrate on hemorrhagic shock-induced lung injury in rats: Implications for testing human blood products in rodents.

Hemorrhagic shock (HS) and trauma can result in an endotheliopathy of trauma, characterized by endothelial compromise, inflammation, and aberrant coagulation. Kcentra, a prothrombin concentrate, has been demonstrated to mitigate pulmonary vascular leak in a murine model of HS. We investigated the effects of Kcentra in a rat model of HS, to achieve physiologic endpoints of relevance. Rats subjected to a grade intravenous splenic injury and controlled hemorrhage for 60 minutes were resuscitated with shed volumes of (1) Lactated Ringer's (LR) solution, (2) LR + 20 IU/kg Kcentra, (3) LR + 50 IU/kg Kcentra, (4) rat fresh frozen plasma (RFFP), or (5) human fresh frozen plasma (HFFP). Blood was harvested for monitoring metabolic and coagulation function. Rat lungs were evaluated for lung injury and permeability. Animals resuscitated with LR displayed a significant increase in pulmonary vascular permeability (sham, 407.9 ± 122.4; shock + LR, 2040 ± 1462). Resuscitation with RFFP (606.5 ± 169.3) reduced leak; however, treatment with Kcentra (HS + Kcentra [20 IU/kg]: 1792 ± 903.4, HS + Kcentra [50 IU/kg]: 1876 ± 1103), and HFFP (1450 ± 533.2) had no significant effect on permeability. Kcentra modestly altered clotting parameters. Metabolic measures, such as lactate, pH, and base deficit, were restored to baseline levels by both RFFP and HFFP, but not Kcentra or LR. Kcentra did not alter pulmonary vascular permeability, but modestly increased clotting potential in injured rats. This suggests that there may be a xenogenic reaction of human products in rats and that the effects of Kcentra on vascular stability may be distinct from its ability to modulate clotting. Our data indicate that the species chosen and utilized for in vivo preclinical testing of human derived blood products is of critical importance in determining their efficacy in animal models and is the primary impetus to communicate these results.

Prostaglandin E2 breaks down pericyte\u2013endothelial cell interaction via EP1 and EP4-dependent downregulation of pericyte N-cadherin, connexin-43, and R-Ras

A close association between pericytes and endothelial cells (ECs) is crucial to the stability and function of capillary blood vessels and microvessels. The loss or dysfunction of pericytes results in significant disruption of these blood vessels as observed in pathological conditions, including cancer, diabetes, stroke, and Alzheimer’s disease. Prostaglandin E2 (PGE2) is a lipid mediator of inflammation, and its tissue concentration is elevated in cancer and neurological disorders. Here, we show that the exposure to PGE2 switches pericytes to a fast-migrating, loosely adhered phenotype that fails to intimately interact with ECs. N-cadherin and connexin-43 in adherens junction and gap junction between pericytes and ECs are downregulated by EP-4 and EP-1-dependent mechanisms, leading to breakdown of the pericyte–EC interaction. Furthermore, R-Ras, a small GTPase important for vascular normalization and vessel stability, is transcriptionally repressed by PGE2 in an EP4-dependent manner. Mouse dermal capillary vessels lose pericyte coverage substantially upon PGE2 injection into the skin. Our results suggest that EP-mediated direct disruption of pericytes by PGE2 is a key process for vascular destabilization. Restoring pericyte–EC interaction using inhibitors of PGE2 signaling may offer a therapeutic strategy in cancer and neurological disorders, in which pericyte dysfunction contributes to the disease progression.

Outcomes and clinical applications of Free Anterolateral thigh Flap as a Reconstructive option for Leg and Foot Defects

lower limb reconstruction remains a big concern as The lower extremity has been recognized for slow wound healing and as an inadequate source of the flap for reconstruction . Great advancements have been made over the past century for reconstructing traumatic and non-traumatic defects in leg and foot. The reconstructive methods ranged from leaving the wound to heal by secondary intention up to free flap.Large defects are commonly reconstructed with free fasciocutaneous flaps or free muscle flaps with skin grafts. The result of a reconstructive operation is mainly due to the vascular component's stability, which is crucial in ensuring the flap survival and proper function. The lower extremity has also been recognized for slow wound healing and as an inadequate source of the flap for reconstruction. In this study, we will present our experience in sohag university hospital In free Antero Lateral Thigh flap used in leg and foot reconstruction as regarding flap outcome, complications.

LCRF-0006, a small molecule mimetic of the N-cadherin antagonist peptide ADH-1, synergistically increases multiple myeloma response to bortezomib.

N‐cadherin is a homophilic cell‐cell adhesion molecule that plays a critical role in maintaining vascular stability and modulating endothelial barrier permeability. Pre‐clinical studies have shown that the N‐cadherin antagonist peptide, ADH‐1, increases the permeability of tumor‐associated vasculature thereby increasing anti‐cancer drug delivery to tumors and enhancing tumor response. Small molecule library screens have identified a novel compound, LCRF‐0006, that is a mimetic of the classical cadherin His‐Ala‐Val sequence‐containing region of ADH‐1. Here, we evaluated the vascular permeability‐enhancing and anti‐cancer properties of LCRF‐0006 using in vitro vascular disruption and cell apoptosis assays, and a well‐established pre‐clinical model (C57BL/KaLwRij/5TGM1) of the hematological cancer multiple myeloma (MM). We found that LCRF‐0006 disrupted endothelial cell junctions in a rapid, transient and reversible manner, and increased vascular permeability in vitro and at sites of MM tumor in vivo. Notably, LCRF‐0006 synergistically increased the in vivo anti‐MM tumor response to low‐dose bortezomib, a frontline anti‐MM agent, leading to regression of disease in 100% of mice. Moreover, LCRF‐0006 and bortezomib synergistically induced 5TGM1 MM tumor cell apoptosis in vitro. Our findings demonstrate the potential clinical utility of LCRF‐0006 to significantly increase bortezomib effectiveness and enhance the depth of tumor response in patients with MM.

OroxylinA reverses lipopolysaccharide-induced adhesion molecule expression and endothelial barrier disruption in the rat aorta

Vascular dysfunction plays a critical role in the pathogenesis of sepsis. We elucidated the mechanisms underlying the amelioration of lipopolysaccharide (LPS)-induced vascular inflammation by oroxylin A (OroA) post-treatment in rats. The animals were intraperitoneally injected with LPS (10 mg/kg) to induce systemic inflammation and intravenously (iv) administered OroA (15 mg/kg) 6 h after the LPS treatment. The assessments included biochemical changes in peripheral blood, vascular reactivity which was evaluated by blood-vessel myography, morphological/histological assessment of inflammation, toll-like receptor (TLR)-4-mediated interleukin-1-receptor-associated-kinase (IRAK)-4 activation, changes in adhesion molecule expression, and endothelial junctional stability in the aorta. LPS significantly enhanced the proinflammatory cytokine release, increased vascular cell adhesion molecule (VCAM)-1 expression, disrupted endothelial tight junction, reduced vascular endothelial barrier stability, and increased macrophage infiltration and accumulation in the aorta. All observed pathological changes and vascular inflammation were significantly reversed by the OroA post-treatment. Importantly, OroA suppressed the increased adhesion molecule expression and the endothelial barrier disruption by inhibiting LPS-activated IRAK-4-targeted inhibitory nuclear factor kappa B kinase (IKK) α/β complex phosphorylation, without directly affecting the interaction between LPS and TLR-4. Moreover, the iNOS activity induced by the LPS challenge was inhibited by the OroA pretreatment of the isolated aortic rings. These results suggest that OroA regulates the vascular tone by inhibiting vascular hyporeactivity caused by NO overproduction and reverses the endothelial barrier dysfunction and inflammation by inhibiting the IRAK-4-mediated IKKα/β phosphorylation. Overall, these findings suggest OroA administration as a potentially useful therapeutic approach for clinical interventions in septic shock.

Cell-specific metabolomic responses to injury: novel insights into blood-brain barrier modulation

On one hand blood-brain barrier (BBB) disturbance aggravates disease progression, on the other it prevents drug access and impedes therapeutic efficacy. Effective ways to modulate barrier function and resolve these issues are sorely needed. Convinced that better understanding of cell-oriented BBB responses could provide valuable insight, and the fact that metabolic dysregulation is prominent in many vascular-related pathological processes associated with BBB disturbance, we hypothesized that differential cell-specific metabolic adaptation majorly influences physiological and pathological barrier functionality. Untargeted liquid chromatography–mass spectrometry (LC-MS) metabolomic profiling was used to obtain individual biochemical fingerprints of primary astrocytes (AC) and brain endothelial cells (EC) during normoxic conditions and increasing hypoxic/ischemic injury and thus a functional readout of cell status. Bioinformatic analyses showed each cell had a distinct metabolic signature. Corroborating their roles in BBB and CNS protection, AC showed an innate ability to dynamically alter their metabolome depending on the insult. Surprisingly, in complete contrast, EC largely maintained their normoxic characteristics in injury situations and their profiles diverged from those of non-brain origin. Tissue specificity/origin is clearly important when considering EC responses. Focusing on energy capacity and utilization we discuss how cell-specific metabolic adaptive capabilities could influence vascular stability and the possibility that altering metabolite levels may be an effective way to modulate brain EC function. Overall this work novel insight into cell-associated metabolic changes, and provides a powerful resource for understanding BBB changes during different injury scenarios.

Compromised angiogenesis and vascular Integrity in impaired diabetic wound healing

Vascular deficits are a fundamental contributing factor of diabetes-associated diseases. Although previous studies have demonstrated that the pro-angiogenic phase of wound healing is blunted in diabetes, a comprehensive understanding of the mechanisms that regulate skin revascularization and capillary stabilization in diabetic wounds is lacking. Using a mouse model of diabetic wound healing, we performed microCT analysis of the 3-dimensional architecture of the capillary bed. As compared to wild type, vessel surface area, branch junction number, total vessel length, and total branch number were significantly decreased in wounds of diabetic mice as compared to WT mice. Diabetic mouse wounds also had significantly increased capillary permeability and decreased pericyte coverage of capillaries. Diabetic wounds exhibited significant perturbations in the expression of factors that affect vascular regrowth, maturation and stability. Specifically, the expression of VEGF-A, Sprouty2, PEDF, LRP6, Thrombospondin 1, CXCL10, CXCR3, PDGFR-β, HB-EGF, EGFR, TGF-β1, Semaphorin3a, Neuropilin 1, angiopoietin 2, NG2, and RGS5 were down-regulated in diabetic wounds. Together, these studies provide novel information about the complexity of the perturbation of angiogenesis in diabetic wounds. Targeting factors responsible for wound resolution and vascular pruning, as well those that affect pericyte recruitment, maturation, and stability may have the potential to improve diabetic skin wound healing.