Maternal Vascular Dysfunction in Congenital Heart Defects

Background:Research on fetal congenital heart defect(CHD)mostly focuses on etiology and mechanisms.However,studies on maternal complications or pathophysiology are limited.Our objective was to determine whether vascular dysfunction exists in pregnant women carrying a fetus with congenital heart defects.Methods:We conducted a case-control study.27 cases of pregnant women carrying a fetus with major CHD admitted to our hospital for delivery between April 2021 and August 2022 were selected.Every case was matched with about 2 pregnant complication-free controls without fetal abnormalities.The proangiogenic and anti-angiogenic factors and pregnancy outcomes were compared.Results:The proangiogenic factors include vascular endothelial growth factor(VEGF)and placental growth factor(PlGF).The anti-angiogenic factors involve soluble fms-like tyrosine kinase 1(sFlt-1)and soluble endoglin(sEng).No differences were found in maternal plasma concentrations of PlGF,VEGF,and sFlt-1 between case-control groups when analyzed at 36 weeks≤gestational age(GA)<39 weeks and 39 weeks≤GA≤41 weeks.The concentrations of sEng in maternal plasma in the fetal CHD group were significantly higher than those in the control group:0.60(0.77)vs.0.32(0.26)ng/ml at 36 weeks≤GA<39 weeks,p=0.001 and 0.75(0.55)vs.0.28(0.27)ng/ml at 39 weeks≤GA≤41 weeks,p<0.001.Conclusion:Vascular dysfunction exists in pregnant women with fetal congenital heart defects,manifesting significantly elevated sEng concentration at delivery.

Vascular dysfunctions and platelet activations by arsenic: two major contributing factors to cardiovascular disease

Arsenic in drinking water is a worldwide health problem that is associated with cardiovascular disease, but the cause is currently unknown. In order to examine whether arsenic affects vasomotor tone in blood vessels, we investigated the effect of arsenic on agonist-induced vasorelaxation and vasoconstriction using the isolated rat aortic rings in in vitro organ bath system. Treatment with inorganic arsenite (AsⅢ) inhibited acetylcholine-induced relaxation of aortic rings by inhibiting production of nitric oxide in endothelium.

Bony connection to vascular dysfunction and implications on hypertension

Bone morphogenic protein 4（BMP4） belongs into the transforming growth factor-β（TGF-β） superfamily.BMP4 was originally discovered to par- ticipate in embryonic development,bone and cartilage formation.BMP4 is up-regulated in calcified atherosclerotic plaques and reduces endothelium-de-pendent relaxations.BMP4 can stimulate superoxide production and exert pro-inflammatory effects on the endothelium.The underlying mechanisms of how BMP4 mediates endothelial dysfunction and hypertension remain to be elucidated.Our recent study shows that BMP treatment led to the impaired en-dothelium -dependent relaxations（EDR）,exaggerated endothelium-dependent contractions（EDC） and reactive oxygen species（ROS） generation in mouse aortas,which were reversed by BMP4 antagonist noggin.Pharmacological inhibition with thromboxane-prostanoid receptor antagonist or cyclooxygenase-2 （COX-2） but not cyclooxygenase-1（COX-1） inhibitor attenuates the BMP4-induced endothelial dysfunction which was further confirmed with the use of COX-1-/- or COX-2-/- mice.Noggin and knockdown of BMP receptor 1A abolished EDC and COX-2 up-regulation in BMP4-treated mouse aortas. Apocynin and tempol treatment were effective in restoring EDR,preventing EDC,eliminating ROS over-production and COX-2 over-expression in BMP4-treated aortae.COX-2 inhibition blocked the effect of BMP4 without affecting BMP4-induced ROS over-production and COX-2 up-regulation.Significantly, renal arteries from hypertensive rats and humans showed higher levels of COX-2 and BMP4 accompanied by endothelial dysfunction.We show for the first time that ROS serve as a pathological link between BMP4 stimulation and the downstream COX-2 up-regulation in endothelial cells,leading to endothelial dysfunction.This BMP4/ROS/COX-2 cascade is important in the maintenance of endothelial dysfunction in hypertension.

Icariin attenuates vascular endothelial dysfunction by inhibiting inflammation through GPER/Sirt1/HMGB1 signaling pathway in type 1 diabetic rats

Icariin, a flavonoid glycoside, is extracted from Epimedium. This study aimed to investigate the vascular protective effects of icariin in type 1 diabetic rats by inhibiting high-mobility group box 1 (HMGB1)-related inflammation and exploring its potential mechanisms. The impact of icariin on vascular dysfunction was assessed in streptozotocin (STZ)-induced diabetic rats through vascular reactivity studies. Western blotting and immunofluorescence assays were performed to measure the expressions of target proteins. The release of HMGB1 and pro-inflammation cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The results revealed that icariin administration enhanced acetylcholine-induced vasodilation in the aortas of diabetic rats. It also notably reduced the release of pro-inflammatory cytokines, including interleukin-8 (IL-8), IL-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) in diabetic rats and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs). The results also unveiled that the pro-inflammatory cytokines in the culture medium of HUVECs could be increased by rHMGB1. The increased release of HMGB1 and upregulated expressions of HMGB1-related inflammatory factors, including advanced glycation end products (RAGE), Toll-like receptor 4 (TLR4), and phosphorylated p65 (p-p65) in diabetic rats and HG-induced HUVECs, were remarkably suppressed by icariin. Notably, HMGB1 translocation from the nucleus to the cytoplasm in HUVECs under HG was inhibited by icariin. Meanwhile, icariin could activate G protein-coupled estrogen receptor (GPER) and sirt1. To explore the role of GPER and Sirt1 in the inhibitory effect of icariin on HMGB1 release and HMGB-induced inflammation, GPER inhibitor and Sirt1 inhibitor were used in this study. These inhibitors diminished the effects of icariin on HMGB1 release and HMGB1-induced inflammation. Specifically, the GPER inhibitor also negated the activation of Sirt1 by icariin. These findings suggest that icariin activates GPER and increases the expression of Sirt1, which in turn reduces HMGB1 translocation and release, thereby improving vascular endothelial function in type 1 diabetic rats by inhibiting inflammation.

Glucagon-like peptide-1 receptor agonists rescued diabetic vascular endothelial damage through suppression of aberrant STING signaling

Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)protect against diabetic cardiovascular diseases and nephropathy.However,their activity in diabetic retinopathy(DR)remains unclear.Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications,suggesting their advantage in DR treatment.By single-cell RNA-sequencing analysis and immunostaining,we observed a high expression of GLP-1R in retinal endothelial cells,which was down-regulated under diabetic conditions.Treatment of GLP-1 RAs significantly restored the receptor expression,resulting in an improvement in retinal degeneration,vascular tortuosity,avascular vessels,and vascular integrity in diabetic mice.GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs.Additionally,the treatment attenuated STING signaling activation in retinal endothelial cells,which is typically activated by leaked mitochondrial DNA.Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes.Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling.This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.

Roles of the Apolipoprotein E Gene and Its Polymorphisms in the Etiopathophysiology of Type 2 Diabetes Mellitus and Its Atherosclerotic Complication in Senegalese Females

Lipid metabolism disorders would be among the components responsible for the risk of the onset of T2DM and its vascular complications. Apolipoprotein E plays an important role in lipid metabolism. We studied the involvement of the APOE gene in the onset of T2DM and its vascular complications. Clinical and biochemical parameters were assessed in each participant. APOE genotypes were identified by PCR-RFLP. Arterial stiffness was studied using a pOpmetre® which evaluates the pulse wave velocity (ft-PWV). Endothelial dysfunction was studied using an EndoPAT2000® which measures endothelium-dependent vasodilation (RHI). In control subjects, the ε3 allele was associated with an increase in fasting blood glucose (r = 2.36, p = 0.018), and a decrease in LDL cholesterol levels (r = −2.17, p = 0.03), and ε4 was associated with an increase in total cholesterol (r = 2.59, p = 0.01), LDL cholesterol (r = 2.84, p = 0.004), and No-HDL cholesterol (r = 2.74, p = 0.006). In type 2 diabetes subjects, the ε2 was associated with a decrease in diastolic blood pressure (r = −2.25, p = 0.02). The ε3 was associated with a decrease in ft-PWV (r = −2.26, p = 0.024) while the ε4 was associated with an increase in ft-PWV (r = 2.52, p = 0.012). Carrying the ε2ε3 genotype would have in 99% a limited risk of developing T2DM, and in event of T2DM, only 1 to 2% would have a significant risk of developing atherosclerosis, which would be severe in 17%. Of the ε2ε4 genotype, 93% had a limited or even possible risk of developing T2DM, the remaining 7% had a very high risk of developing T2DM. Diabetics carrying ε2ε4 had in 7% very high risk of developing atherosclerosis. The latter had a 20% very high risk of being very severe. Subjects carrying the ε3ε4 genotype had a 67% possible or even probable risk of developing T2DM and in the event of diabetes, there was in 34% very high risk of developing atherosclerosis which will not have even the time to evolve towards severity. For subjects carrying the ε3ε3, the risk of developing T2DM and athérosclerosis was higher than that of the ε2ε3, and ε2ε4 genotypes but lower than that ε3ε4 genotype. The physio-pathological role of the APOE gene and the impacts of its polymorphisms are important in the onset and progression of type 2 diabetes mellitus.

Vasospastic angina in women: Clinical backgrounds and prognoses of patients younger than and older than 60 years

BACKGROUND We frequently encounter cases of women with vasospastic angina(VSA).Additionally,some women with VSA are younger than 60 years old.However,it is unknown whether the characteristics of VSA in women aged<60 years are different from those in women aged≥60 years.AIM To investigate and compare the clinical characteristics and prognosis of VSA in women aged<60 years from those in women aged≥60 years.METHODS We enrolled 94 women with VSA who were diagnosed using the spasm provocation test.According to the age at diagnosis,the patients were divided into two groups:Group Y(age<60 years,n=17)and Group O(age≥60 years,n=77).Flow-mediated dilation(FMD)and nitroglycerin(NTG)-induced dilation(NID)of the brachial artery were performed and assessed using brachial ultrasonography.Moreover,conventional coronary risk factors,such as atherosclerotic lesions(stenosis>20%)detected using coronary angiography and focal spasms(coronary spasm within one segment of one coronary artery),and major cardiovascular adverse events(MACE)were assessed in both groups.RESULTS Smoking was more prevalent in Group Y than in Group O(P=0.04).FMD was similar in both groups(Group O:4.3%±3.2%,Group Y:4.5%±3.3%;P=0.75),whereas NID was higher in Group Y(20.5%±8.6%)than in Group O(13.6%±5.3%,P<0.01).Atherosclerosis was not detected in Group Y but was detected in Group O(61%,P<0.01).Focal spasms were less frequent in Group Y(12%)than in Group O(38%,P=0.04).The incidence of major adverse cardiac events did not differ between the two groups(P=0.40).CONCLUSIONWomen aged < 60 years with VSA have less atherosclerotic lesions and focal spasms. These characteristicsmay be affected by smoking habits and vascular smooth muscle dysfunction.

In depth understanding of retinitis pigmentosa pathogenesis through optical coherence tomography angiography analysis:a narrative review

Retinitis pigmentosa(RP)is the most recognized inherited retinal disorder involving progressive photoreceptors degeneration which eventually causes blindness.However,the pathogenesis of RP is still unclear,making it difficult to establish satisfying treatments.Evidence have been found to support the theory that vascular dysfunction is associated with the progression of RP.Optical coherence tomography angiography(OCTA)is a newly developed technology that enables visualization as well as quantitative assessment of retinal and choroidal vasculature noninvasively.Advances in OCTA have opened a window for indepth understanding of RP pathogenesis.Here,we propose a hypothesis of RP pathogenesis based on the current OCTA findings in RP,which includes four stages and two important key factors,vascular dysfunction and microglia activation.Further,we discuss the future animal experiments needed and how advanced OCTA technology can help to further verity the hypothesis.The final goal is to explore potential treatment options with enhanced understanding of RP pathogenesis.

Electroacupuncture for the prevention of postoperative gastrointestinal dysfunction in patients undergoing vascular surgery under general anesthesia: study protocol for a prospective practical randomized controlled trial

BACKGROUND： Postoperative gastrointestinal dysfunction（PGD） is one of the most common complications following major surgeries under general anesthesia（GA）. Despite ongoing research and new drug treatments, abdominal distension within 24 h postoperatively occurs in 8%–28% of all surgeries. We aim to analyze the effectiveness of preventing PGD by preoperatively stimulating Neiguan（PC6）, Zusanli（ST36） and Shangjuxu（ST37） bilaterally twice a day compared with sham-acupuncture treatment and standard treatment.METHODS AND DESIGN： This is a single-center, prospective practical randomized controlled trial. All groups will be given standard treatments. Patients undergoing vascular surgery under GA will be included from the Vascular Surgery Unit in West China Hospital of Sichuan University, China, and divided into three groups. The experimental group will receive routine treatments and acupuncture at PC6, ST36 and ST37 bilaterally with electrical stimulation twice a day for 20 min preoperatively. The sham-acupuncture group will receive pseudo-electroacupuncture at sham acupoints of PC6, ST36 and ST37, which are 1 cun away from the real acupoints. The routine-treatment group will not receive electroacupuncture. The outcomes include the incidence of abdominal distention, abdominal circumference, the degree of abdominal distension, the fi rst time of fl atus and defecation, and hospitalization duration. DISCUSSION： The results from this study will demonstrate whether preoperative electroacupuncture is an effective method for the prevention of PGD in patients undergoing vascular surgery under GA. This study may also provide a standardized acupuncture treatment for reduction of PGD. TRIAL REGISTRATION： This study is registered with the Chinese Clinical Trial Registry： Chi CTR-TRC-13003649.

Potentiation of NETs release is novel characteristic of TREM-1 activation and the pharmacological inhibition of TREM-1 could prevent from the deleterious consequences of NETs release in sepsis

During sepsis,neutrophil activation induces endothelial cell(EC)dysfunction partly through neutrophil extracellular trap(NET)release.The triggering receptor expressed on myeloid cell-1(TREM-1)is an orphan immune receptor that amplifies the inflammatory response mediated by Toll-like receptor-4(TLR4)engagement.Although the key role of TLR4 signaling in NETosis is known,the role of TREM-1 in this process has not yet been investigated.Here,we report that TREM-1 potentiates NET release by human and murine neutrophils and is a component of the NET structure.In contrast,pharmacologic inhibition or genetic ablation of TREM-1 decreased NETosis in vitro and during experimental septic shock in vivo.Moreover,isolated NETs were able to activate ECs and impair vascular reactivity,and these deleterious effects were dampened by TREM-1 inhibition.TREM-1 may,therefore,constitute a new therapeutic target to prevent NETosis and associated endothelial dysfunction.

Hypertension and osteoporosis:Common pathophysiological mechanisms

Hypertension is a common disease affecting almost one half of adults and is a major cause of morbiditiy and mortality.Substantial epidemiological data suggest that there is a relationship between hypertension and osteoporosis although the underlying mechanisms remain poorly defined.It is now clear that inflammation and immune activation contribute to the end-organ damage that occurs in hypertension,and that factors in the hypertensive environment,including increased sympathetic outflow,cytokines,angiotensin II,oxidative stress and vascular disease can affect bone metabolism and the balance between bone generation and resorption.Many of these events likely contribute to osteoporosis.In this review we will consider these factors and discuss potential diagnostic and therapeutic measures that might be implemented to improve these diseases.

Effect of Serum from Overfatigue Rats on JNK/c-Jun/HO-1 Pathway in Human Umbilical Vein Endothelial Cells and the Intervening Effect of Tongxinluo(通心络)Superfine Powder

Objective:To cultivate human umbilical vein endothelial cells (HUVECs) in the serum of overfatigue rats with the intervention of Tongxinluo (通心络) superfine powder (TXLSP).By examining the variation of the activity of JNK/c-Jun/HO-1 pathway,the possible mechanisms of vascular endothelial dysfunction under overfatigue conditions and the intervening effect of TXLSP were explored.Methods:The HUVECs were randomly divided into the normal control group,the model group,the SP600125 (a specific antagonist of JNK)gro...

Influence of electroacupuncture on ghrelin and the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthase signaling pathway in spontaneously hypertensive rats

Objective To investigate the influence of electroacupuncture(EA)on ghrelin and the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthase(PI3K/Akt/eNOS)signaling pathway in spontaneously hypertensive rats(SHRs).Methods Eight Wistar-Kyoto rats were used as the healthy blood pressure(BP)control(normal group),and 32 SHRs were randomized into model group,EA group,EA plus ghrelin group(EA+G group),and EA plus PF04628935 group(a potent ghrelin receptor blocker;EA+P group)using a random number table.Rats in the normal group and model group did not receive treatment,but were immobilized for 20 min per day,5 times a week,for 4 continuous weeks.SHRs in the EA group,EA+G group and EA+P group were immobilized and given EA treatment in 20 min sessions,5 times per week,for 4 weeks.Additionally,1 h before EA,SHRs in the EA+G group and EA+P group were intraperitoneally injected with ghrelin or PF04628935,respectively,for 4 weeks.The tail-cuff method was used to measure BP.After the 4-week intervention,the rats were sacrificed by cervical dislocation,and pathological morphology of the abdominal aorta was observed using hematoxylin-eosin(HE)staining.Enzyme-linked immunosorbent assay(ELISA)was used to detect the levels of ghrelin,nitric oxide(NO),endothelin-1(ET-1)and thromboxane A2(TXA2)in the serum.Isolated thoracic aortic ring experiment was performed to evaluate vasorelaxation.Western blot was used to measure the expression of PI3K,Akt,phosphorylated Akt(p-Akt)and eNOS proteins in the abdominal aorta.Further,quantitative real-time polymerase chain reaction(qRT-PCR)was conducted to measure the relative levels of mRNA expression for PI3K,Akt and eNOS in the abdominal aorta.Results EA significantly reduced the systolic BP(SBP)and diastolic BP(DBP)(P<0.05).HE staining showed that EA improved the morphology of the vascular endothelium to some extent.Results of ELISA indicated that higher concentrations of ghrelin and NO,and lower concentrations of ET-1 and TXA2 were present in the EA group(P<0.05).The isolated thoracic aortic ring experiment demonstrated that the vasodilation capacity of the thoracic aorta increased in the EA group.Results of Western blot and qRT-PCR showed that EA increased the abundance of PI3K,p-Akt/Akt and eNOS proteins,as well as expression levels of PI3K,Akt and eNOS mRNAs(P<0.05).In the EA+G group,SBP and DBP decreased(P<0.05),ghrelin concentrations increased(P<0.05),and the concentrations of ET-1 and TXA2 decreased(P<0.05),relative to the EA group.In addition,the levels of PI3K and eNOS proteins,the p-Akt/Akt ratio,and the expression of PI3K,Akt and eNOS mRNAs increased significantly in the EA+G group(P<0.05),while PF04628935 reversed these effects.Conclusion EA effectively reduced BP and protected the vascular endothelium,and these effects may be linked to promoting the release of ghrelin and activation of the PI3K/Akt/eNOS signaling pathway.