Mechanisms of skin vascular maturation and maintenance captured by longitudinal imaging of live mice.

A functional network of blood vessels is essential for organ growth and homeostasis, yet how the vasculature matures and maintains homeostasis remains elusive in live mice. By longitudinally tracking the same neonatal endothelial cells (ECs) over days to weeks, we found that capillary plexus expansion is driven by vessel regression to optimize network perfusion. Neonatal ECs rearrange positions to evenly distribute throughout the developing plexus and become positionally stable in adulthood. Upon local ablation, adult ECs survive through a plasmalemmal self-repair response, while neonatal ECs are predisposed to die. Furthermore, adult ECs reactivate migration to assist vessel repair. Global ablation reveals coordinated maintenance of the adult vascular architecture that allows for eventual network recovery. Lastly, neonatal remodeling and adult maintenance of the skin vascular plexus are orchestrated by temporally restricted, neonatal VEGFR2 signaling. Our work sheds light on fundamental mechanisms that underlie both vascular maturation and adult homeostasis in vivo.

Cyclic stretch promotes vascular homing of endothelial progenitor cells via Acsl1 regulation of mitochondrial fatty acid oxidation.

Endothelial progenitor cells (EPCs) play an important role in vascular repair and re-endothelialization after vessel injury. EPCs in blood vessels are subjected to cyclic stretch (CS) due to the pulsatile pressure, but the role of CS in metabolic reprogramming of EPC, particularly its vascular homing and repair, is largely unknown. In the current study, physiological CS applied to EPCs at a magnitude of 10% and a frequency of 1 Hz significantly promoted their vascular adhesion and endothelial differentiation. CS enhanced mitochondrial elongation and oxidative phosphorylation (OXPHOS), as well as adenosine triphosphate production. Metabolomic study and Ultra-high performance liquid chromatography-mass spectrometry assay revealed that CS significantly decreased the content of long-chain fatty acids (LCFAs) and markedly induced long-chain fatty acyl-CoA synthetase 1 (Acsl1), which in turn facilitated the catabolism of LCFAs in mitochondria via fatty acid ß-oxidation and OXPHOS. In a rat carotid artery injury model, transplantation of EPCs overexpressing Acsl1 enhanced the adhesion and re-endothelialization of EPCs in vivo. MRI and vascular morphology staining showed that Acsl1 overexpression in EPCs improved vascular repair and inhibited vascular stenosis. This study reveals a mechanotransduction mechanism by which physiological CS enhances endothelial repair via EPC patency.

Chronic social defeat alters brain vascular-associated cell gene expression patterns leading to vascular dysfunction and immune system activation.

Brain vascular integrity is critical for brain health, and its disruption is implicated in many brain pathologies, including psychiatric disorders. Brain-vascular barriers are a complex cellular landscape composed of endothelial, glial, mural, and immune cells. Yet currently, little is known about these brain vascular-associated cells (BVACs) in health and disease. Previously, we demonstrated that 14 days of chronic social defeat (CSD), a mouse paradigm that produces anxiety and depressive-like behaviors, causes cerebrovascular damage in the form of scattered microbleeds. Here, we developed a technique to isolate barrier-related cells from the mouse brain and subjected the isolated cells to single-cell RNA sequencing. Using this isolation technique, we found an enrichment in BVAC populations, including distinct subsets of endothelial and microglial cells. In CSD compared to non-stress, home-cage control, differential gene expression patterns disclosed biological pathways involving vascular dysfunction, vascular healing, and immune system activation. Overall, our work demonstrates a unique technique to study BVAC populations from fresh brain tissue and suggests that neurovascular dysfunction is a key driver of psychosocial stress-induced brain pathology.

Association of electronic cigarette use with circulating angiogenic cell levels in healthy young adults: Evidence for chronic systemic injury.

BACKGROUND: Circulating angiogenic cells (CACs) are indicative of vascular health and repair capacity; however, their relationship with chronic e-cigarette use is unclear. This study aims to assess the association between e-cigarette use and CAC levels. METHODS: We analyzed CAC levels in 324 healthy participants aged 21-45 years from the cross-sectional Cardiovascular Injury due to Tobacco Use study in four groups: never tobacco users (n = 65), sole e-cigarette users (n = 19), sole combustible cigarette users (n = 212), and dual users (n = 28). A total of 15 CAC subpopulations with four cell surface markers were measured using flow cytometry: CD146 (endothelial), CD34 (stem), CD45 (leukocyte), and AC133 (early progenitor/stem). Generalized linear models with gamma distribution and log-link were generated to assess association between CACs and smoking status. Benjamini-Hochberg were used to adjust p-values for multiple comparisons. RESULTS: The cohort was 47% female, 51% Black/African American, with a mean (± SD) age of 31 ± 7 years. Sole cigarette use was significantly associated with higher levels of two endothelial marker CACs (Q ⩽ 0.05). Dual users had higher levels of four endothelial marker CACs and one early progenitor/stem marker CAC (Q ⩽ 0.05). Sole e-cigarette users had higher levels of one endothelial and one leukocyte marker CAC (Q ⩽ 0.05). CONCLUSION: Dual use of e-cigarettes and combustible cigarettes was associated with higher levels of endothelial origin CACs, indicative of vascular injury. Sole use of e-cigarettes was associated with higher endothelial and inflammatory CACs, suggesting ongoing systemic injury. Distinct patterns of changes in CAC subpopulations suggest that CACs may be informative biomarkers of changes in vascular health due to tobacco product use.

Postoperative antiplatelet and/or anticoagulation use does not impact complication or reintervention rates after vein repair of arterial injury: A PROOVIT study.

INTRODUCTION: The use of antiplatelet (AP) and anticoagulation (AC) therapy after autogenous vein repair of traumatic arterial injury is controversial. The hypothesis in this study was that there is no difference in early postoperative outcomes regardless of whether AC, AP, both, or neither are used. METHODS: The American Association for the Surgery of Trauma (AAST) PROspective Observational Vascular Injury Treatment (PROOVIT) registry was queried from November, 2013, to January, 2019, for arterial injuries repaired with a vein graft. Demographics and injury characteristics were compared. Need for in-hospital reoperation was the primary outcome in this four-arm study, assessed with two ordinal logistic regression models (1. no therapy vs. AC only vs. AC and AP; 2. no therapy vs. AP only vs. AC and AP). RESULTS: 373 patients (52 no therapy, 88 AP only, 77 AC only, 156 both) from 19 centers with recorded Injury Severity Scores (ISS) were identified. Patients who received no therapy were younger than those who received AP (27.0 vs. 34.2, p = 0.02), had higher transfusion requirement (p < 0.01 between all groups) and a different distribution of anatomic injury (p < 0.01). After controlling for age, sex, ISS, platelet count, hemoglobin, pH, lactate, INR, transfusion requirement and anatomic location, there was no association with postoperative medical therapy and in-hospital operative reintervention, or any secondary outcome, including thrombosis (p = 0.67, p = 0.22). CONCLUSIONS: Neither AC nor AP alone, nor in combination, impact complication rate after arterial repair with autologous vein. These patients can be safely treated with or without antithrombotics, recognizing that this study did not demonstrate a beneficial effect.

Decreased Serum Stromal Cell-Derived Factor-1 in Patients with Familial Hypercholesterolemia and Its Strong Correlation with Lipoprotein Subfractions.

Stromal cell-derived factor-1 (SDF-1) is a chemokine that exerts multifaceted roles in atherosclerosis. However, its association with hyperlipidemia is contradictory. To date, serum SDF-1 and its correlations with lipid fractions and subfractions in heterozygous familial hypercholesterolemia (HeFH) have not been investigated. Eighty-one untreated patients with HeFH and 32 healthy control subjects were enrolled in the study. Serum SDF-1, oxidized LDL (oxLDL) and myeloperoxidase (MPO) were determined by ELISA. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Significantly lower serum SDF-1 was found in HeFH patients compared to healthy controls. Significant negative correlations were detected between serum total cholesterol, triglycerides, LDL-cholesterol (LDL-C), apolipoprotein B100 (ApoB100) and SDF-1. Furthermore, serum SDF-1 negatively correlated with VLDL and IDL, as well as large LDL and large and intermediate HDL subfractions, while there was a positive correlation between mean LDL-size, small HDL and SDF-1. SDF-1 negatively correlated with oxLDL and MPO. A backward stepwise multiple regression analysis showed that the best predictors of serum SDF-1 were VLDL and oxLDL. The strong correlation of SDF-1 with lipid fractions and subfractions highlights the potential common pathways of SDF-1 and lipoprotein metabolism, which supports the role of SDF-1 in atherogenesis.

Exosomes Derived from Endothelial Cells Inhibit Neointimal Hyperplasia Induced by Carotid Artery Injury in Rats via ROS-NLRP3 Inflammasome Pathway.

This study attempted to investigate whether exosomes derived from rat endothelial cells (EC-Exo) attenuate intimal hyperplasia after balloon injury using hematoxylin and eosin staining, immunohistochemistry, immunofluorescence staining, Evans blue staining, and Western blotting. The results indicated that EC-Exo inhibited intimal hyperplasia in the carotid artery after balloon injury, promoted re-endothelialization, and reduced vascular inflammation and ROS-NLRP3-mediated cell pyroptosis. Thus, EC-Exo can inhibit neointimal hyperplasia after carotid artery injury in rats presumably by inhibiting the ROS-NLRP3 inflammasome and phenotypic transformation of vascular smooth muscle cells.

CCR2 monocytes repair cerebrovascular damage caused by chronic social defeat stress.

Immune surveillance of the brain plays an important role in health and disease. Peripheral leukocytes patrol blood-brain barrier interfaces, and after injury, monocytes cross the cerebrovasculature and follow a pattern of pro- and anti-inflammatory activity leading to tissue repair. We have shown that chronic social defeat (CSD) causes scattered vasculature disruptions. Here, we assessed CCR2+ monocyte trafficking to the vascular injury sites in Ccr2wt/rfp reporter mice both during CSD and one week following CSD cessation. We found that CSD for 14 days induced microhemorrhages where plasma fibrinogen leaked into perivascular spaces, but it did not affect the distribution or density of CCR2rfp+ monocytes in the brain. However, after recovery from CSD, many vascularly adhered CCR2+ cells were detected, and gene expression of the CCR2 chemokine receptor ligands CCL7 and CCL12, but not CCL2, was elevated in endothelial cells. Adhered CCR2+ cells were mostly the non-classical, anti-inflammatory Ly6Clo type, and they phagocytosed fibrinogen in perivascular spaces. In CCR2-deficient Ccr2rfp/rfp mice, fibrinogen levels remained elevated in recovery. Fibrinogen infused intracerebroventricularly induced CCR2+ cells to adhere to the vasculature and phagocytose perivascular fibrinogen in Ccr2wt/rfp but not Ccr2rfp/rfp mice. Depletion of monocytes with clodronate liposomes during CSD recovery prevented fibrinogen clearance and blocked behavioral recovery. We hypothesize that peripheral CCR2+ monocytes are not elevated in the brain on day 14 at the end of CSD and do not contribute to its behavioral effects at that time, but in recovery following cessation of stress, they enter the brain and exert restorative functions mediating vascular repair and normalization of behavior.

Vascular injuries: Aetiology, presentation and management outcomes at a tertiary hospital in Lagos, Nigeria.

Vascular injuries lead to haemorrhagic shock and distal limb ischaemia, especially with an arterial injury. This life-threatening state mandates urgent evaluation and intervention to save life and limbs. The treatment aims to restore blood flow and replace lost blood within the golden hours, stabilising cardiovascular haemodynamics and averting irreversible ischaemic damage. The aim of this study was to analyse the clinical profile of vascular injuries, management and outcomes in our institution. Materials and Methods: This retrospective study covered the period from January 2015 to December 2021. Information of interest were extracted from the medical records of each participant. The results from the data analysis were presented in charts and tables. Results: Seventy-four patients aged 15-78 years (mean 32.30 ± 13.75 years) were included in this study. The male-to-female ratio was 3.6:1. The most common causes were gunshot injury, road traffic accident and iatrogenic injuries. The mean duration from injury to presentation was 9.85 h and mean duration from presentation to restoration of flow was 7.3 h. The most common injured artery was the femoral artery, whereas the most common vein was inferior vena cava. Primary vascular repair was done in majority of the cases. Amputation was performed in 18.9% with loss of viability of the limb. Conclusion: Vascular injury though relatively uncommon remains a challenging and life-threatening disease predominantly in young adult males. Urgent intervention prevents limb loss and mortality. Favourable outcome is accomplished by improving emergency healthcare delivery and well-equipped vascular centres with adequately trained personnel in the nation's hospitals.

Salvage of Injured Lower Limb and Improvement of Quality of Life of a 1½-Year-Old Child.

We present a case of left proximal femoral artery transection injury in 1½-year-old male child due to a fall over a bike handle after sustaining a road traffic accident. He was presented to the emergency room with a cut proximal end of the left femoral artery and a fracture upper end of the shaft of the femur seen at the wound site. Following initial resuscitation, the patient was planned for wound exploration, fracture stabilization, and femoral artery repair which were executed, and salvage of the lower limb of 1½-year-old child was achieved. We conclude that teamwork, training, and experience in repairing pediatric vessels and timely pediatric vascular repair play a pivotal role in the salvage of a limb and improvement of the quality of life of a child.

Long noncoding RNA p21 enhances autophagy to alleviate endothelial progenitor cells damage and promote endothelial repair in hypertension through SESN2/AMPK/TSC2 pathway.

Vascular damage of hypertension has been the focus of hypertension treatment, and endothelial progenitor cells (EPCs) play an important role in the repair of vascular endothelial damage. Functional damage and decreased number of EPCs are observed in the peripheral circulation of hypertensive patients, but its mechanism is not yet elucidated. Here, we show that the number of EPCs in hypertensive patients is significantly lower than that of normal population, and the cell function decreases with a higher proportion of EPCs at later stages. A decrease in autophagy is responsible for the senescence and damage of EPCs induced by AngII. Moreover, lncRNA-p21 plays a critical regulator role in EPCs' senescence and dysfunction. Furthermore, lncRNA-p21 activates SESN2/AMPK/TSC2 pathway by promoting the transcriptional activity of p53 and enhances autophagy to protect against AngII-induced EPC damage. The data provide evidence that a reversal of decreased autophagy serves as the protective mechanism of EPC injury in hypertensive patients, and lncRNA-p21 is a new therapeutic target for vascular endothelial repair in hypertension.

Vascular repairs in gynecologic operations are uncommon but predict major morbidity and mortality.

OBJECTIVE: Gynecologic surgery has potential for adjunct vascular interventions, given the proximity of major intra-abdominal and pelvic blood vessels. Our goal was to determine contemporary incidence, associations, and outcomes of vascular repairs in gynecologic operations. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database (2005-2017) was queried for patients undergoing elective gynecologic operations. Vascular repairs were performed concurrently or during reoperation. Univariable and multivariable analyses evaluated associations with vascular repairs and 30-day morbidity. RESULTS: A total of 201,224 gynecologic operations were identified: hysterectomy (88.3%), myomectomy (5.9%), adnexal surgery (3.5%), vulvovaginectomy/other (1.1%), nonadnexal tumor or cyst excision (0.5%), ectopic pregnancy treatment (0.4%), and pelvic lymphadenectomy (0.3%). There were 187 vascular repairs in 176 (0.09%) patients. Repairs were typically concurrent (89.8%) and most commonly included open abdominal blood vessel repair (51.8%), major abdominal artery ligation (25%), vena cava reconstruction/ligation (6%), common iliac vein ligation (4.2%), and aorta/great vessel repair (4.2%). A minority were performed endovascularly (1.7%). Patients undergoing vascular repairs were older (56 vs 46 years), were more likely to have an open vs minimally invasive/vaginal operation (71.6% vs 28.4%), and were more likely to have a hysterectomy (85.2%; P < .001 for all). In multivariable analysis, vascular repairs were observed more often with hysterectomy (odds ratio [OR]; 7.63, 95% confidence interval [CI], 2.28-25.55; P = .001) and open vs minimally invasive/vaginal operations (OR, 5.24; 95% CI, 2.64-10.42; P < .001). Vascular repairs were also more common for patients with malignant disease (OR, 2.84; 95% CI, 1.78-4.53; P < .001), patients assigned to American Society of Anesthesiologists class 3 or class 4 (OR, 1.85; CI, 1.36-2.53; P = .002), and patients without obesity (OR, 1.45; 95% CI, 1.08-1.96; P = .014). Vascular repairs independently predicted major morbidity and mortality (OR, 7.26; 95% CI, 5.26-10.03; P < .001) after adjustment for open operative approach, American Society of Anesthesiologists class 3 or class 4, and hysterectomy. CONCLUSIONS: Whereas vascular repairs during gynecologic operations are rare, they are associated with morbidity and mortality. These findings provide an evidence base for risk assessment and informed consent.

Pro- and antiangiogenic therapies: current status and clinical implications.

Blood vessels nurture every part of the human body. Consequently, abnormalities in the vasculature are closely associated with a variety of diseases, including cerebral stroke, heart disease, retinopathy, and cancer. Pro- or antiangiogenic therapies can influence these diseases by regulating the growth of new blood vessels from a pre-existing vascular network or dampening excessive blood growth. However, clinical translation of these approaches is slow and challenging. In this review, we discuss recent preclinical approaches to regulate angiogenesis and their potential and risks in a clinical setting.-Rust, R., Gantner, C., Schwab, M. E. Pro- and antiangiogenic therapies: current status and clinical implications.

The Role of Macrophages in Vascular Repair and Regeneration after Ischemic Injury.

Macrophage is one of the important players in immune response which perform many different functions during tissue injury, repair, and regeneration. Studies using animal models of cardiovascular diseases have provided a clear picture describing the effect of macrophages and their phenotype during injury and regeneration of various vascular beds. Many data have been generated to demonstrate that macrophages secrete many important factors including cytokines and growth factors to regulate angiogenesis and arteriogenesis, acting directly or indirectly on the vascular cells. Different subsets of macrophages may participate at different stages of vascular repair. Recent findings also suggest a direct interaction between macrophages and other cell types during the generation and repair of vasculature. In this short review, we focused our discussion on how macrophages adapt to the surrounding microenvironment and their potential interaction with other cells, in the context of vascular repair supported by evidences mostly from studies using hindlimb ischemia as a model for studying post-ischemic vascular repair.

Vascular repair after firearm injury is associated with increased morbidity and mortality.

OBJECTIVE: Firearm injuries have high morbidity and mortality. Presentation of injuries requiring concurrent vascular repair and its outcomes are unclear. Our study's objective was to characterize the injury details and to assess the associated mortality and morbidity after vascular repair. METHODS: The National Inpatient Sample was queried from 1993 to 2014 for all firearm injuries. International Classification of Diseases, Ninth Revision codes were used to identify firearm injuries and those who also underwent a vascular repair. Multivariable analysis was used to assess the effect of a concurrent vascular repair on outcomes. RESULTS: There were 648,662 firearm injuries identified; 63,973 (9.9%) involved a vascular repair. Overall, 88.7% of patients were male, and Medicaid was the most common insurance (40.2%). Intents were assault or legal intervention (60%), unintentional (24.2%), and suicide (8.6%). Patients undergoing vascular repair were younger, more often of black race and male sex, and on Medicaid insurance, with a lower household income and assault/legal intent (P < .005). Patients who underwent vascular repair had a higher frequency of abdomen/pelvis and extremity injuries as well as an elevated New Injury Severity Score (P < .005). Patients with vascular repair were more frequently treated at urban, teaching, and large hospitals (P < .005). Overall mortality rate was 2.2%; patients who underwent vascular repair had a higher mortality compared with those without (5.51% vs 1.98%; P < .001). Patients with vascular repair had higher rates of acute renal failure (3.1% vs 0.8%), venous thromboembolic events (0.5% vs 0.3%), pulmonary-related events (0.6% vs 0.28%), cardiac-related events (0.8% vs 0.2%), sepsis (1.4% vs 0.5%), and any complication (5.7% vs 2%; all P < .0001). Vascular repair was independently associated with mortality (odds ratio [OR], 2.68; 95% confidence interval [CI], 2.43-2.95; P < .0001). Age older than 46 years (OR, 2.01; 95% CI, 1.71-2.35; P < .0001), male sex (OR, 1.15; 95% CI, 1.05-1.25; P = .003), self-pay/no insurance (OR, 1.6; 95% CI, 1.47-1.75; P < .0001), suicide intent (OR, 3.73; 95% CI, 3.36-4.13; P < .0001), unintentional intent (OR, 1.12; 95% CI, 1.03-1.22; P < .0001), head/neck location (OR, 13.9; 95% CI, 12.5-15.6; P < .0001), Northeast region, and New Injury Severity Score >4 were independently associated with in-hospital mortality. Vascular repair was also independently associated with any complication (OR, 2.12; 95% CI, 1.98-2.28; P < .0001). CONCLUSIONS: Firearm injuries with vascular repair were independently associated with higher injury severity score and mortality. A majority of vascular repairs were performed for injury to the abdomen/pelvis and extremity with assault/legal intent, whereas head and neck injury and suicide intent were the least frequent.

Elevating ATP-binding cassette transporter G1 improves re-endothelialization function of endothelial progenitor cells via Lyn/Akt/eNOS in diabetic mice.

Endothelial progenitor cell (EPC) dysfunction contributes to diabetes-induced delay in endothelium repair after vessel injury, prominently associated with diabetic cardiovascular complications such as neointima formation. ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol efflux to HDL, which may favorably affect EPC function. However, whether ABCG1 improves EPC function, especially in diabetes, remains unknown. Here we investigated the role of ABCG1 in EPCs by using Tie2-mediated ABCG1 transgenic (Tie2- ABCG1Tg) mice. Mice were injected with streptozotocin to induce diabetes mellitus. As compared with wild-type (WT) mice, in Tie2- ABCG1Tg mice, diabetes-impaired EPC migration and tube formation were reversed. In vitro gain-of-function and loss-of-function studies further revealed that ABCG1-overexpressing EPCs showed increased migration and tube formation and differentiation via the Lck/Yes-related novel protein tyrosine kinase /Akt/endothelial NO synthase pathway by enhancing cellular cholesterol efflux. Finally, type 1 and type 2 diabetic mouse models with arterial injury were intravenously injected with labeled EPCs from WT or Tie2- ABCG1Tg mice. Re-endothelialization in diabetic mice was improved to a greater extent by injection of ABCG1-overexpressing than WT EPCs. Our study demonstrated that ABCG1 in EPCs improved repair after vascular injury in diabetes by increasing EPC function such as migration, tube formation and differentiation, and subsequent re-endothelialization. ABCG1 might be a promising therapeutic target for diabetes-associated vascular diseases.-Shi, Y., Lv, X., Liu, Y., Li, B., Liu, M., Yan, M., Liu, Y., Li, Q., Zhang, X., He, S., Zhu, M., He, J., Zhu, Y., Zhu, Y., Ai, D. Elevating ATP-binding cassette transporter G1 improves re-endothelialization function of endothelial progenitor cells via Lyn/Akt/eNOS in diabetic mice.

[Neurovascular complications in fractures of the extremities, part 1 : Vascular lesions]. / Neurovaskuläre Komplikationen bei Frakturen der Extremitäten, Teil 1 : Gefäßläsionen.

Neurovascular injuries in fractures threaten at least the function of extremities. The timely interaction between diagnosis and treatment of vascular injuries helps to avoid a poor outcome or even fatal complications. An important parameter is to "think about it" for injuries under strain. An ankle-brachial index (ABI) of <0.9 is an indicator. Massive bleeding, manifest and long-lasting peripheral ischemia and a rapidly expanding hematoma necessitate an immediate surgical intervention. Endovascular techniques are recommended on the extremities of stable patients with circumscribed vascular lesions. The debate about the sequence of repair (vascular vs. osseous) has to be decided on an individual basis; however, when in doubt vascular repair should be given priority. Vessel reconstructions should be performed without tension and must be covered by vital soft tissues, the indications for fasciotomy should be liberally interpreted. The prognosis with respect to preservation of the extremity and long-term functional outcome substantially depends on the quality of treatment of accompanying injuries.

Nogo-A inhibits vascular regeneration in ischemic retinopathy.

Nogo-A is a potent glial-derived inhibitor of axon growth in the injured CNS and acts as a negative regulator of developmental angiogenesis by inhibiting vascular endothelial cell migration. However, its function in pathological angiogenesis has never been studied after ischemic injury in the CNS. Using the mouse model of oxygen-induced retinopathy (OIR) which yields defined zones of retinal ischemia, our goal was to investigate the role of Nogo-A in vascular regeneration. We demonstrate a marked upregulation of the Nogo-A receptor sphingosine 1-phosphate receptor 2 in blood vessels following OIR, while Nogo-A is abundantly expressed in surrounding glial cells. Acute inhibition of Nogo-A with function-blocking antibody 11C7 significantly improved vascular regeneration and consequently prevented pathological pre-retinal angiogenesis. Ultimately, inhibition of Nogo-A led to restoration of retinal function as determined by electrophysiological response of retinal cells to light stimulation. Our data suggest that anti-Nogo-A antibody may protect neuronal cells from ischemic damage by accelerating blood vessel repair in the CNS. Targeting Nogo-A by immunotherapy may improve CNS perfusion after vascular injuries.

Peripheral post-ischemic vascular repair is impaired in a murine model of Alzheimer's disease.

The pathophysiology of sporadic Alzheimer's disease (AD) remains uncertain. Along with brain amyloid-ß (Aß) deposits and neurofibrillary tangles, cerebrovascular dysfunction is increasingly recognized as fundamental to the pathogenesis of AD. Using an experimental model of limb ischemia in transgenic APPPS1 mice, a model of AD (AD mice), we showed that microvascular impairment also extends to the peripheral vasculature in AD. At D70 following femoral ligation, we evidenced a significant decrease in cutaneous blood flow (- 29%, P < 0.001), collateral recruitment (- 24%, P < 0.001), capillary density (- 22%; P < 0.01) and arteriole density (- 28%; P < 0.05) in hind limbs of AD mice compared to control WT littermates. The reactivity of large arteries was not affected in AD mice, as confirmed by unaltered size, and vasoactive responses to pharmacological stimuli of the femoral artery. We identified blood as the only source of Aß in the hind limb; thus, circulating Aß is likely responsible for the impairment of peripheral vasculature repair mechanisms. The levels of the majority of pro-angiogenic mediators were not significantly modified in AD mice compared to WT mice, except for TGF-ß1 and PlGF-2, both of which are involved in vessel stabilization and decreased in AD mice (P = 0.025 and 0.019, respectively). Importantly, endothelin-1 levels were significantly increased, while those of nitric oxide were decreased in the hind limb of AD mice (P < 0.05). Our results suggest that vascular dysfunction is a systemic disorder in AD mice. Assessment of peripheral vascular function may therefore provide additional tools for early diagnosis and management of AD.

Oleuropein attenuates hydrogen peroxide-induced autophagic cell death in human adipose-derived stem cells.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells with self-renewing properties; thus, transplanting functionally enhanced MSCs might be a promising strategy for cell therapy against ischemic diseases. However, extensive oxidative damage in ischemic tissue affects the cell fate of transplanted MSCs, eventually resulting in cell damage and autophagic cell death. Oleuropein (OLP) is a bioactive compound isolated from olives and olive oil that harbors antioxidant properties. This study aimed to investigate the potential cytoprotective effects of OLP against oxidative stress and autophagic cell death in MSCs. We found that short-term priming with OLP attenuated H2O2-induced apoptosis by regulating the pro-apoptotic marker Bax and the anti-apoptotic markers Bcl-2 and Mcl-1. Notably, OLP inhibits H2O2 -induced autophagic cell death by modulating autophagy-related death signals, including mTOR (mammalian target of rapamycin), ULK1 (unc-51 like autophagy activating kinase 1), Beclin-1, AMPK (AMP-activated protein kinase), and LC3 (microtubule-associated protein 1a/1b-light chain 3). Our data suggest that OLP might reduce H2O2-induced autophagy and cell apoptosis in MSCs by regulating both the AMPK-ULK axis and the Bcl-2-Mcl-1 axis. Consequently, short-term cell priming with OLP might enhance the therapeutic effect of MSCs against ischemic vascular diseases, which provides an important potential improvement for emerging therapeutic strategies.