CCL4 contributes to aging related angiogenic insufficiency through activating oxidative stress and endothelial inflammation.

Aging is a natural process associated with chronic inflammation in the development of vascular dysfunction. We hypothesized that chemokine C-C motif ligands 4 (CCL4) might play a vital role in aging-related vascular dysfunction. Circulating CCL4 was up-regulated in elderly subjects and in aged animals. CCL4 inhibition reduced generation of reactive oxygen species (ROS), attenuated inflammation, and restored cell functions in endothelial progenitor cells from elderly subjects and in aged human aortic endothelial cells. CCL4 promoted cell aging, with impaired cell functioning, by activating ROS production and inflammation. CCL4 knockout mice and therapeutic administration of anti-CCL4 neutralizing antibodies exhibited vascular and dermal anti-aging effects, with improved wound healing, via the down-regulation of inflammatory proteins and the activation of angiogenic proteins. Altogether, our findings suggested that CCL4 may contribute to aging-related vascular dysfunction via activating oxidative stress and endothelial inflammation. CCL4 may be a potential therapeutic target for vascular protections during aging.

Gestational influenza A virus infection elicits nonresolving vascular dysfunction and T-cell accumulation in the aorta of mice.

T-cell accumulation within the aorta promotes endothelial dysfunction and the genesis of cardiovascular disease, including hypertension and atherosclerosis. Viral infection during pregnancy is also known to mediate marked acute endothelial dysfunction, but it is not clear whether T cells are recruited to the aorta and whether the dysfunction persists postpartum. Here, we demonstrate that influenza A virus (IAV) infection during pregnancy in a murine model resulted in endothelial dysfunction of the aorta, which persisted for up to 60 days postinfection and was associated with higher levels of IFN-γ mRNA expression within the tissue. In the absence of infection, low numbers of naïve CD4+ and CD8+ T cells, central memory T cells, and effector memory T cells were observed in the aorta. However, with IAV infection, these T-cell subsets were significantly increased with a notable accumulation of IAV-specific CD8+ effector memory T cells. Critically, this increase was maintained out to at least 60 days. In contrast, IAV infection in nonpregnant female mice resulted in modest endothelial dysfunction with no accumulation of T cells within the aorta. These data, therefore, demonstrate that the aorta is a site of T-cell recruitment and retention after IAV infection during pregnancy. Although IAV-specific memory T cells could theoretically confer protection against future influenza infection, nonspecific memory T-cell activation and IFN-γ production in the aorta could also contribute to future endothelial dysfunction and cardiovascular disease.NEW & NOTEWORTHY Pregnancy is a risk factor for cardiovascular complications to influenza A virus (IAV) infection. We demonstrate that gestational IAV infection caused endothelial dysfunction of the maternal aorta, which persisted for 60 days postinfection in mice. Various T cells accumulated within the aorta at 60 days because of the infection, and this was associated with elevated levels of the proinflammatory cytokine, IFN-γ. Our study demonstrates a novel "long influenza" cardiovascular phenotype in female mice.

Sitting leg vasculopathy: potential adaptations beyond the endothelium.

Increased sitting time, the most common form of sedentary behavior, is an independent risk factor for all-cause and cardiovascular disease mortality; however, the mechanisms linking sitting to cardiovascular risk remain largely elusive. Studies over the last decade have led to the concept that excessive time spent in the sitting position and the ensuing reduction in leg blood flow-induced shear stress cause endothelial dysfunction. This conclusion has been mainly supported by studies using flow-mediated dilation in the lower extremities as the measured outcome. In this review, we summarize evidence from classic studies and more recent ones that collectively support the notion that prolonged sitting-induced leg vascular dysfunction is likely also attributable to changes occurring in vascular smooth muscle cells (VSMCs). Indeed, we provide evidence that prolonged constriction of resistance arteries can lead to modifications in the structural characteristics of the vascular wall, including polymerization of actin filaments in VSMCs and inward remodeling, and that these changes manifest in a time frame that is consistent with the vascular changes observed with prolonged sitting. We expect this review will stimulate future studies with a focus on VSMC cytoskeletal remodeling as a potential target to prevent the detrimental vascular ramifications of too much sitting.

PEG10 viral aspartic protease domain is essential for the maintenance of fetal capillary structure in the mouse placenta.

The therian-specific gene paternally expressed 10 (Peg10) plays an essential role in placenta formation: Peg10 knockout mice exhibit early embryonic lethality as a result of severe placental defects. The PEG10 protein exhibits homology with long terminal repeat (LTR) retrotransposon GAG and POL proteins; therefore, we generated mice harboring a mutation in the highly conserved viral aspartic protease motif in the POL-like region of PEG10 because this motif is essential for the life cycle of LTR retrotransposons/retroviruses. Intriguingly, frequent perinatal lethality, not early embryonic lethality, was observed with fetal and placental growth retardation starting mid-gestation. In the mutant placentas, severe defects were observed in the fetal vasculature, where PEG10 is expressed in the three trophoblast cell layers that surround fetal capillary endothelial cells. Thus, Peg10 has essential roles, not only in early placenta formation, but also in placental vasculature maintenance from mid- to late-gestation. This implies that along the feto-maternal placenta interface an interaction occurs between two retrovirus-derived genes, Peg10 and retrotransposon Gag like 1 (Rtl1, also called Peg11), that is essential for the maintenance of fetal capillary endothelial cells.

Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2/ET-1 axis-controlled ERK1/2 pathway.

BACKGROUND: NADPH oxidase (NOX), a primary source of endothelial reactive oxygen species (ROS), is considered a key event in disrupting the integrity of the blood-retinal barrier. Abnormalities in neurovascular-coupled immune signaling herald the loss of ganglion cells in glaucoma. Persistent microglia-driven inflammation and cellular innate immune system dysregulation often lead to deteriorating retinal degeneration. However, the crosstalk between NOX and the retinal immune environment remains unresolved. Here, we investigate the interaction between oxidative stress and neuroinflammation in glaucoma by genetic defects of NOX2 or its regulation via gp91ds-tat. METHODS: Ex vivo cultures of retinal explants from wildtype C57BL/6J and Nox2 -/- mice were subjected to normal and high hydrostatic pressure (Pressure 60 mmHg) for 24 h. In vivo, high intraocular pressure (H-IOP) was induced in C57BL/6J mice for two weeks. Both Pressure 60 mmHg retinas and H-IOP mice were treated with either gp91ds-tat (a NOX2-specific inhibitor). Proteomic analysis was performed on control, H-IOP, and treatment with gp91ds-tat retinas to identify differentially expressed proteins (DEPs). The study also evaluated various glaucoma phenotypes, including IOP, retinal ganglion cell (RGC) functionality, and optic nerve (ON) degeneration. The superoxide (O2-) levels assay, blood-retinal barrier degradation, gliosis, neuroinflammation, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative PCR were performed in this study. RESULTS: We found that NOX2-specific deletion or activity inhibition effectively attenuated retinal oxidative stress, immune dysregulation, the internal blood-retinal barrier (iBRB) injury, neurovascular unit (NVU) dysfunction, RGC loss, and ON axonal degeneration following H-IOP. Mechanistically, we unveiled for the first time that NOX2-dependent ROS-driven pro-inflammatory signaling, where NOX2/ROS induces endothelium-derived endothelin-1 (ET-1) overexpression, which activates the ERK1/2 signaling pathway and mediates the shift of microglia activation to a pro-inflammatory M1 phenotype, thereby triggering a neuroinflammatory outburst. CONCLUSIONS: Collectively, we demonstrate for the first time that NOX2 deletion or gp91ds-tat inhibition attenuates iBRB injury and NVU dysfunction to rescue glaucomatous RGC loss and ON axon degeneration, which is associated with inhibition of the ET-1/ERK1/2-transduced shift of microglial cell activation toward a pro-inflammatory M1 phenotype, highlighting NOX2 as a potential target for novel neuroprotective therapies in glaucoma management.

Oxidative stress and vascular dysfunction: Potential therapeutic targets and therapies in peripheral artery disease.

Peripheral artery disease (PAD) is the manifestation of atherosclerosis characterized by the accumulation of plaques in the arteries of the lower limbs. Interestingly, growing evidence suggests that the pathology of PAD is multifaceted and encompasses both vascular and skeletal muscle dysfunctions, which contributes to blunted physical capabilities and diminished quality of life. Importantly, it has been suggested that many of these pathological impairments may stem from blunted reduction-oxidation (redox) handling. Of note, in those with PAD, excessive production of reactive oxygen species (ROS) outweighs antioxidant capabilities resulting in oxidative damage, which may have systemic consequences. It has been suggested that antioxidant supplementation may be able to assist in handling ROS. However, the activation of various ROS production sites makes it difficult to determine the efficacy of these antioxidant supplements. Therefore, this review focuses on the common cellular mechanisms that facilitate ROS production and discusses how excessive ROS may impair vascular and skeletal muscle function in PAD. Furthermore, we provide insight for current and potential antioxidant therapies, specifically highlighting activation of the Kelch-like ECH-associated protein 1 (Keap1) - Nuclear Factor Erythroid 2-related factor 2 (Nrf2) pathway as a potential pharmacological therapy to combat ROS accumulation and aid in vascular function, and physical performance in patients with PAD. Altogether, this review provides a better understanding of excessive ROS in the pathophysiology of PAD and enhances our perception of potential therapeutic targets that may improve vascular function, skeletal muscle function, walking capacity, and quality of life in patients with PAD.

Systemic C-peptide supplementation ameliorates retinal neurodegeneration by inhibiting VEGF-induced pathological events in diabetes.

Diabetic retinopathy (DR) is caused by retinal vascular dysfunction and neurodegeneration. Intraocular delivery of C-peptide has been shown to be beneficial against hyperglycemia-induced microvascular leakage in the retina of diabetes; however, the effect of C-peptide on diabetes-induced retinal neurodegeneration remains unknown. Moreover, extraocular C-peptide replacement therapy against DR to avoid various adverse effects caused by intravitreal injections has not been studied. Here, we demonstrate that systemic C-peptide supplementation using osmotic pumps or biopolymer-conjugated C-peptide hydrogels ameliorates neurodegeneration by inhibiting vascular endothelial growth factor-induced pathological events, but not hyperglycemia-induced vascular endothelial growth factor expression, in the retinas of diabetic mice. C-peptide inhibited hyperglycemia-induced activation of macroglial and microglial cells, downregulation of glutamate aspartate transporter 1 expression, neuronal apoptosis, and histopathological changes by a mechanism involving reactive oxygen species generation in the retinas of diabetic mice, but transglutaminase 2, which is involved in retinal vascular leakage, is not associated with these pathological events. Overall, our findings suggest that systemic C-peptide supplementation alleviates hyperglycemia-induced retinal neurodegeneration by inhibiting a pathological mechanism, involving reactive oxygen species, but not transglutaminase 2, in diabetes.

An electron paramagnetic resonance time-course study of oxidative stress in the plasma of electronic cigarette exposed rats.

The long-term consequences of electronic cigarette (Ecig) use in humans are not yet known, but it is known that Ecig aerosols contain many toxic compounds of concern. We have recently shown that Ecig exposure impairs middle cerebral artery (MCA) endothelial function and that it takes 3 days for MCA reactivity to return to normal. However, the sources contributing to impairment of the endothelium were not investigated. We hypothesized that the increased levels of oxidative stress markers in the blood are correlated with impaired MCA reactivity. We used electron paramagnetic resonance (EPR) spectroscopy to examine plasma from 4-month-old male Sprague-Dawley rats that were exposed to either air (n = 5) or 1 h Ecig exposure, after which blood samples were collected at varying times after exposure (i.e., 1-4, 24, 48 and 72 h postexposure, n = 4 or 5 in each time group). The EPR analyses were performed using the redox-sensitive hydroxylamine spin probe 1-hydroxy-3-carboxymethyl-2,2,5,5-tetramethyl-pyrrolidine (CMH) to measure the level of reactive oxidant species in the plasma samples. We found that EPR signal intensity from the CM• radical was significantly increased in plasma at 1-4, 24 and 48 h (P < 0.05, respectively) and returned to control (air) levels by 72 h. When evaluating the EPR results with MCA reactivity, we found a significant negative correlation (Pearson's P = 0.0027). These data indicate that impaired cerebrovascular reactivity resulting from vaping is associated with the oxidative stress level (measured by EPR from plasma) and indicate that a single 1 h vaping session can negatively influence vascular health for up to 3 days after vaping. HIGHLIGHTS: What is the central question of this study? Does the time course of oxidative stress triggered by electronic cigarette exposure follow the cerebral vascular dysfunction? What is the main finding and its importance? Electron paramagnetic resonance analysis shows that the oxidative stress induced after a single 1 h exposure to electronic cigarette aerosol takes ≤72 h to return to normal, which mirrors the time course for vascular dysfunction in the middle cerebral artery that we have reported previously.

Spatiotemporal Control of Vascular CaV1.2 by α1C S1928 Phosphorylation.

BACKGROUND: L-type CaV1.2 channels undergo cooperative gating to regulate cell function, although mechanisms are unclear. This study tests the hypothesis that phosphorylation of the CaV1.2 pore-forming subunit α1C at S1928 mediates vascular CaV1.2 cooperativity during diabetic hyperglycemia. METHODS: A multiscale approach including patch-clamp electrophysiology, super-resolution nanoscopy, proximity ligation assay, calcium imaging' pressure myography, and Laser Speckle imaging was implemented to examine CaV1.2 cooperativity, α1C clustering, myogenic tone, and blood flow in human and mouse arterial myocytes/vessels. RESULTS: CaV1.2 activity and cooperative gating increase in arterial myocytes from patients with type 2 diabetes and type 1 diabetic mice, and in wild-type mouse arterial myocytes after elevating extracellular glucose. These changes were prevented in wild-type cells pre-exposed to a PKA inhibitor or cells from knock-in S1928A but not S1700A mice. In addition, α1C clustering at the surface membrane of wild-type, but not wild-type cells pre-exposed to PKA or P2Y11 inhibitors and S1928A arterial myocytes, was elevated upon hyperglycemia and diabetes. CaV1.2 spatial and gating remodeling correlated with enhanced arterial myocyte Ca2+ influx and contractility and in vivo reduction in arterial diameter and blood flow upon hyperglycemia and diabetes in wild-type but not S1928A cells/mice. CONCLUSIONS: These results suggest that PKA-dependent S1928 phosphorylation promotes the spatial reorganization of vascular α1C into "superclusters" upon hyperglycemia and diabetes. This triggers CaV1.2 activity and cooperativity, directly impacting vascular reactivity. The results may lay the foundation for developing therapeutics to correct CaV1.2 and arterial function during diabetic hyperglycemia.

A High Cholesterol Diet During Late Pregnancy Impairs Long-Term Maternal Vascular Function in Mice.

BACKGROUND: Gestational dyslipidemia is associated with pregnancy complications including preeclampsia. However, whether gestational dyslipidemia leads postpartum vascular dysfunction, which could increase the risk for cardiovascular complications later in life, is not known. Here, we aimed to determine whether a gestational dyslipidemia affects postpartum vascular health and induces early signs of atherosclerosis. METHODS: Pregnant C57BL/6 mice received a high cholesterol diet or control diet from gestational day 13.5 until term. After delivery, all mice received the control diet for ≈3 months postpartum (PP). Age-matched nulliparous females were on the same diets for equal periods. After 3 months, all mice were euthanized, serum was collected, and aortas were isolated to assess vascular function (wire myography) and markers of oxidative stress and early atherosclerosis. RESULTS: PP-high cholesterol diet females had increased circulating cholesterol levels compared with PP-control diet mice, without effect of the diet in nulliparous mice. Methacholine-induced vasodilation was impaired, and nitric oxide contribution reduced, by the high cholesterol diet in aortas of PP mice, but not in nulliparous mice. Exposure to oxidized low-density-protein cholesterol further impaired methylcholine-induced vasodilation in PP-high cholesterol diet aortas only. Compared with PP-control diet mice, aortic inducible nitric oxide synthase expression, reactive oxygen species and nitrotyrosine levels were increased in aortas from PP-high cholesterol diet mice. No differences in aortic lipid deposition and macrophage infiltration were found. CONCLUSIONS: Exposure to a high cholesterol diet in pregnancy impairs vascular function postpartum. Our results support the hypothesis that gestational dyslipidemia impacts maternal vascular function after pregnancy, which could potentially predispose these women to future cardiovascular complications.

C-Phycoerythrin Prevents Chronic Kidney Disease-Induced Systemic Arterial Hypertension, Avoiding Oxidative Stress and Vascular Dysfunction in Remanent Functional Kidney.

Chronic kidney disease (CKD) is a burden in low- and middle-income countries, and a late diagnosis with systemic arterial hypertension (SAH) is the major complication of CKD. C-phycoerythrin (CPE) is a bioactive compound derived from Phormidium persicinum that presents anti-inflammatory and antioxidant effects in vitro and nephroprotective effects in vivo. In the current study, we determine the antihypertensive effect of CPE in a 5/6 nephrectomy-induced CKD model using twenty normotensives male Wistar rats, grouped into four groups (n = 5): sham; sham + CPE; 5/6 nephrectomy (NFx); and NFx + CPE. Treatment started a week post-surgery and continued for five weeks, with weekly hemodynamic evaluations. Following treatment, renal function, oxidative stress, and the expression of vascular dysfunction markers were assessed. The renal function analysis revealed CKD hyperfiltration, and the hemodynamic evaluation showed that SAH developed at the third week. AT1R upregulation and AT2R downregulation together with Mas1/p-Akt/p-eNOS axis were also observed. CPE treatment mitigated renal damage, preserved renal function, and prevented SAH with the modulation of the vasodilative AT1R, AT2R, and Mas1/pAKT/peNOS axis. This result reveals that CPE prevented CKD progression to SAH by avoiding oxidative stress and vascular dysfunction in the kidneys.

Chorio-retinal vessel density in women affected by functional hypothalamic amenorrhea: a monocentric observational cross-sectional study to evaluate the impact of hypoestrogenism on chorio-retinal vascularization.

PURPOSE: Functional hypothalamic amenorrhea (FHA) is characterized by an estrogen deficiency which in turn can cause vascular dysfunction. The aim of this study is to evaluate any changes in the chorio-retinal circulation in patients affected by FHA. 24 patients with FHA and 24 age-matched controls underwent a gynecological evaluation and an OCT angiography (OCTA) to study chorio-retinal vascularization. RESULTS: OCTA in FHA patients showed an increase in vessel density in the choriocapillaris (CC) layer (both in the fovea area, at 5% p value = 0.037 and in the whole area, at 5% p value = 0.028) and an increase in vascular density in the deep fovea (DVP) (at 10% p value = 0.096) in the whole district compared to controls. Simple linear regressions show a significant negative association between CC vessel density and insulin (p = 0.0002) and glucose values (p = 0.0335) for the fovea district and a negative association between DVP vessel density and endometrial thickness (at 10%, p value: 0.095) in the whole district. CONCLUSION: Our study shows that CC vessel density is increased in women affected by FHA. This could represent a compensation effort to supply the vascular dysfunction caused by estrogen deficiency. We also found an increasing trend in vascular density in DVP associated with the decrease of endometrial thickness, an indirect sign of estrogenization. Considering that these changes occur in absence of visual defects, they could be used as a biomarker to estimate hypoestrogenism-induced microcirculation changes before clinical appearance.

Evaluation of choroidal thickness and optic disc parameters in patients with chronic phase gout.

PURPOSE: This study aims to assess the disparities in choroidal thickness and optic disc parameters between individuals diagnosed with chronic gout and an age- and gender-matched control cohort. METHODS: This cross-sectional study involved 30 gout patients receiving treatment at the Rheumatology clinic, alongside 30 healthy control individuals matched for age and gender. A comprehensive ophthalmological assessment, encompassing visual acuity measurement, intraocular pressure evaluation, slit-lamp biomicroscopy, and dilated fundus examination, was conducted for all participants. Peripapillary retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), and subfoveal choroidal thickness (SFCT) were quantified utilizing Spectral Domain Optical Coherence Tomography. RESULTS: The mean age within the study group was 54.53 ± 9.43 years, while the control group's mean age was 53.20 ± 10.36 years. In both the gout and control cohorts, there were 28 men and 2 women. No significant differences were observed in age and gender between the groups. Gout patients manifested thinner RNFL and GCC across all quadrants; however, statistically significant thinning was only evident in the nasal and inferior quadrants for RNFL. Despite a thinner SFCT observed in gout patients compared to controls, this discrepancy did not attain statistical significance. CONCLUSION: Chronic phase gout patients may display alterations in optic disc and macular parameters, alongside potential variations in choroidal thickness. Nevertheless, more controlled studies encompassing a larger participant pool are imperative to substantiate our findings.

Effect of aortic smooth muscle BK channels on mediating chronic intermittent hypoxia-induced vascular dysfunction.

Chronic intermittent hypoxia (CIH) can lead to vascular dysfunction and increase the risk of cardiovascular diseases, cerebrovascular diseases, and arterial diseases. Nevertheless, mechanisms underlying CIH-induced vascular dysfunction remain unclear. Herein, this study analyzed the role of aortic smooth muscle calciumactivated potassium (BK) channels in CIH-induced vascular dysfunction. CIH models were established in rats and rat aortic smooth muscle cells (RASMCs). Hemodynamic parameters such as mean blood pressure (MBP), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were measured in rats, along with an assessment of vascular tone. NO and ET-1 levels were detected in rat serum, and the levels of ET-1, NO, eNOS, p-eNOS, oxidative stress markers (ROS and MDA), and inflammatory factors (IL-6 and TNF-α) were tested in aortic tissues. The Ca2+ concentration in RASMCs was investigated. The activity of BK channels (BKα and BKß) was evaluated in aortic tissues and RASMCs. SBP, DBP, and MBP were elevated in CIH-treated rats, along with endothelial dysfunction, cellular edema and partial detachment of endothelial cells. BK channel activity was decreased in CIH-treated rats and RASMCs. BK channel activation increased eNOS, p-eNOS, and NO levels while lowering ET-1, ROS, MDA, IL-6, and TNF-α levels in CIH-treated rats. Ca2+ concentration increased in RASMCs following CIH modeling, which was reversed by BK channel activation. BK channel inhibitor (Iberiotoxin) exacerbated CIH-induced vascular disorders and endothelial dysfunction. BK channel activation promoted vasorelaxation while suppressing vascular endothelial dysfunction, inflammation, and oxidative stress, thereby indirectly improving CIH-induced vascular dysfunction.

Pathological mechanisms of cigarette smoking, dietary, and sedentary lifestyle risks in vascular dysfunction: mitochondria as a common target of risk factors.

In the past century, the lifespan of the human population has dramatically increased to the 80 s, but it is hindered by a limited health span to the 60 s due to an epidemic increase in the cardiovascular disease which is a main cause of morbidity and mortality. We cannot underestimate the progress in understanding the major cardiovascular risk factors which include cigarette smoking, dietary, and sedentary lifestyle risks. Despite their clinical significance, these modifiable risk factors are still the major contributors to cardiovascular disease. It is, therefore, important to understand the specific molecular mechanisms behind their pathological effects to develop new therapies to improve the treatment of cardiovascular disease. In recent years, our group and others have made a progress in understanding how these risk factors can promote endothelial dysfunction, smooth muscle dysregulation, vascular inflammation, hypertension, lung, and heart diseases. These factors, despite differences in their nature, lead to stereotypical alterations in vascular metabolism and function. Interestingly, cigarette smoking has a tremendous impact on a very distant site from the initial epithelial exposure, namely circulation and vascular cells mediated by a variety of stable cigarette smoke components which promote vascular oxidative stress and alter vascular metabolism and function. Similarly, dietary and sedentary lifestyle risks facilitate vascular cell metabolic reprogramming promoting vascular oxidative stress and dysfunction. Mitochondria are critical in cellular metabolism, and in this work, we discuss a new concept that mitochondria are a common pathobiological target for these risk factors, and mitochondria-targeted treatments may have a therapeutic effect in the patients with cardiovascular disease.

Amyloid beta peptides (Aß) from Alzheimer's disease neuronal secretome induce endothelial activation in a human cerebral microvessel model.

In Alzheimer's disease (AD), secretion and deposition of amyloid beta peptides (Aß) have been associated with blood-brain barrier dysfunction. However, the role of Aß in endothelial cell (EC) dysfunction remains elusive. Here we investigated AD mediated EC activation by studying the effect of Aß secreted from human induced pluripotent stem cell-derived cortical neurons (hiPSC-CN) harboring a familial AD mutation (Swe+/+) on human brain microvascular endothelial cells (HBMECs) in 2D and 3D perfusable microvessels. We demonstrated that increased Aß levels in Swe+/+ conditioned media (CM) led to stress fiber formation and upregulation of genes associated with endothelial inflammation and immune-adhesion. Perfusion of Aß-rich Swe+/+ CM induced acute formation of von Willebrand factor (VWF) fibers in the vessel lumen, which was attenuated by reducing Aß levels in CM. Our findings suggest that Aß peptides can trigger rapid inflammatory and thrombogenic responses within cerebral microvessels, which may exacerbate AD pathology.

High-plasma soluble prorenin receptor is associated with vascular damage in male, but not female, mice fed a high-fat diet.

Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 wk to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and ANG II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 wk in females fed either an NFD or HFD. Significant sex differences were found after 28 wk of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and ANG II. T2DM in males was accompanied by nondipping hypertension, carotid artery stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and systolic blood pressure. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex.NEW & NOTEWORTHY High-fat diet (HFD) for 28 wk leads to type 2 diabetes mellitus (T2DM) phenotype, concomitant with increased plasma soluble prorenin receptor (sPRR), nondipping blood pressure, and vascular stiffness in male mice. HFD-fed female mice exhibiting a preserved cardiometabolic phenotype until ovariectomy revealed increased plasma sPRR and blood pressure. Plasma sPRR may indicate the status of systemic renin-angiotensin-aldosterone system (RAAS) activation and the onset of vascular complications during T2DM in a sex-dependent manner.

Estrogen ameliorates sepsis-induced vascular hyporeactivity in thoracic aorta of female rats via permissive effect of GRα expression.

OBJECTIVE: Estrogen is correlated to the lower mortality and disease severity of female than that of male, which indicates the potential therapeutic role of estrogen supplement therapy in sepsis. The structure of Daidzein is similar to that of 17ß estradiol (E2), an estrogen in human body, causing the exogenous Daidzein can interact with estrogen receptor as well as E2 in the body. We aim to explore the therapeutic role of estrogen in sepsis-induced vascular dysfunction. Also, we wonder if estrogen regulates blood pressure via glucocorticoid-mediated vascular reactivity. METHODS: Female SD rats received ovariectomy (OVX) to induce estrogen deficiency. After 12 weeks of administration, cecal ligation and puncture (CLP) was used to establish the in vivo model of sepsis. Lipopolysaccharide (LPS) was used to construct the in vitro model of sepsis in vascular smooth muscle cells (VSMCs). E2 and Daidzein were used for estrogen supplement therapy. RESULTS: E2 and Daidzein significantly inhibited inflammation infiltration and histopathological injury in thoracic aorta in the rat model with CLP. E2 and Daidzein improved carotid pressure and vascular hyporeactivity in sepsis rats with OVX. Importantly, E2 and Daidzein promoted glucocorticoid permissive action and increased glucocorticoid receptor α (GRα) expression in thoracic aorta smooth muscle cells. E2 and Daidzein upregulated GRα, and inhibits cytokine production, proliferative phenotype and cell migration in LPS-induced VSMCs. CONCLUSION: Estrogen improved vascular hyporeactivity in thoracic aorta induced by sepsis via permissive effect of GRα expression.

Role of c-Src and reactive oxygen species in cardiovascular diseases.

Oxidative stress, caused by the over production of oxidants or inactivity of antioxidants, can modulate the redox state of several target proteins such as tyrosine kinases, mitogen-activated protein kinases and tyrosine phosphatases. c-Src is one such non-receptor tyrosine kinase which activates NADPH oxidases (Noxs) in response to various growth factors and shear stress. Interaction between c-Src and Noxs is influenced by cell type and primary messengers such as angiotensin II, which binds to G-protein coupled receptor and activates the intracellular signaling cascade. c-Src stimulated activation of Noxs results in elevated release of intracellular and extracellular reactive oxygen species (ROS). These ROS species disturb vascular homeostasis and cause cardiac hypertrophy, coronary artery disease, atherosclerosis and hypertension. Interaction between c-Src and ROS in the pathobiology of cardiac fibrosis is hypothesized to be influenced by cell type and stimuli. c-Src and ROS have a bidirectional relationship, thus increased ROS levels due to c-Src mediated activation of Noxs can further activate c-Src by promoting the oxidation and sulfenylation of critical cysteine residues. This review highlights the role of c-Src and ROS in mediating downstream signaling pathways underlying cardiovascular diseases. Furthermore, due to the central role of c-Src in activation of various signaling proteins involved in differentiation, migration, proliferation, and cytoskeletal reorganization of vascular cells, it is presented as therapeutic target for treating cardiovascular diseases except cardiac fibrosis.

Vascular Dysfunction in Polycystic Kidney Disease: A Mini-Review.

Polycystic kidney disease (PKD) is one of the most common hereditary kidney diseases, which is characterized by progressive cyst growth and secondary hypertension. In addition to cystogenesis and renal abnormalities, patients with PKD can develop vascular abnormalities and cardiovascular complications. Progressive cyst growth substantially alters renal structure and culminates into end-stage renal disease. There remains no cure beyond renal transplantation, and treatment options remain largely limited to chronic renal replacement therapy. In addition to end-stage renal disease, patients with PKD also present with hypertension and cardiovascular disease, yet the timing and interactions between the cardiovascular and renal effects of PKD progression are understudied. Here, we review the vascular dysfunction found in clinical and preclinical models of PKD, including the clinical manifestations and relationship to hypertension, stroke, and related cardiovascular diseases. Finally, our discussion also highlights the critical questions and emerging areas in vascular research in PKD.