Preliminary Studies Of Macrovascular And Microvascular Disease In Inflammatory Bowel Disease

Background and Objective: Inflammatory bowel disease(IBD)includes Crohn’s disease(CD)and ulcerative colitis(UC)and is characterized by chronic and recurrent intestinal inflammation.IBD patients greatly benefit from the pursuit of symptom relief to endoscopic and histological healing.IBD might require lifelong disease management,including nutritional assessment and guidance,colorectal cancer screening,and multiple organ function monitoring.IBD not only affects the gastrointestinal tract but also may involve many other organs of the body,such as the cardiovascular system,kidney,liver,skin,and mucosa.Involvement of organs outside the gastrointestinal tract are usually termed extraintestinal manifestations(EIMs)of IBD.EIMs can significantly impact the quality of life of IBD patients,sometimes more so than the intestinal disease.Considering the gastrointestinal and EIMs in IBD patients,a multidisciplinary team approach should be considered for IBD patients.Several population-based studies have shown that IBD patients have an increased risk of cardiovascular diseases,including coronary artery disease,peripheral artery disease,stroke,mesenteric artery disease,and venous thromboembolism.To our knowledge,no literature has reported the aortic endothelial function,and liver and renal vascular permeability in colitis models.The present study aimed to summarize the endothelial function in IBD patients by meta-analysis and to investigate the macrovascular and microvascular function in DSS-induced colitis model.Methods:(1)A Meta-analysis will be registered with PROSPERO.The meta-analysis will be performed on clinical studies to evaluate endothelial function,arterial stiffness,and carotid intima-media thickness in patients with IBD,after searching Pub Med,Embase,Cochrane library,and Web of Science databases.All statistical analyses were conducted using Stata 17.0 software.(2)Acute and chronic colitis models were induced in male and female mice with DSS treatment.Aortic wall stiffness,endothelial function,ROS levels,plasma levels of pro-inflammatory cytokines,blood pressure,vascular permeability,microvascular density,as well as mitochondrial function were evaluated.Transabdominal ultrasound imaging of the abdominal aorta was conducted to evaluate the aortic wall stiffness.The thoracic,abdominal,and femoral aorta were mounted to a multi-wire myograph system to evaluate endothelial function.Limb blood flow was measured noninvasively using a laser doppler perfusion imaging system.Vascular permeability was evaluated by Evans blue assay.(3)pAKT/e NOS pathway proteins were analyzed by Western blotting.The isolated mitochondria were incubated by Seahorse analyzer to evaluate respiratory chain function.The ultrastructural changes in kidney and liver were evaluated by electron microscopy.Results:(1)The carotid-femoral pulse wave velocity was significantly higher in patients with IBD compared to that in matched controls.Compared to matched control subjects,the augmentation index was also significantly increased in patients with IBD.Brachial artery flow-mediated dilatation was significantly decreased in patients with IBD than that in matched controls.It was found that c IMT was significantly increased in patients with IBD as compared with that in matched controls.(2)There were no differences in the aortic distensibility,pulse wave velocity,and blood pressure between colitis models and controls.There were no differences in endothelium-dependent relaxation or endotheliumindependent relaxation of thoracic and abdominal aorta in either male or female mice with and without acute DSS-induced colitis.Endotheliumdependent relaxation and endothelium-independent relaxation of thoracic aorta remained intact in both male and female mice with DSS-induced chronic colitis.However,endothelium-dependent relaxation of abdominal aorta was significantly reduced in female mice but not in male mice with chronic colitis mice.The maximal relaxation was significantly reduced in chronic female colitis mice.There were no significant differences in ROS levels in fresh aortic cross-sections of either thoracic or abdominal aorta in male and female mice with acute or chronic colitis.There were no differences in blood flow recovery(ischemic limb blood perfusion/normal limb blood perfusion),functional score,and ischemia score in mice with and without colitis.No differences in vascular density and ROS levels were observed in the gastrocnemius muscle of the ischemic limb in mice with or without colitis.Contraction and relaxation of femoral artery remained intact in female mice with DSS-induced chronic colitis.In DSS-induced acute colitis model,the vascular permeability was increased in colon,kidney,and liver tissue of female mice,while only the vascular permeability in the colon increased in male mice.In DSS-induced chronic colitis model,the vascular permeability was increased in colon,kidney,and liver tissue of both female and male mice.(3)The p-AKT and e NOS protein expression levels were increased in tissues with increased vascular permeability.The plasma creatinine levels were increased in both female and male chronic colitis models.HE staining images revealed cellular edema in the renal interstitial region in colitis model.The proteomics data of kidney tissue showed that differential proteins between controls and colitis models were related to mitochondrial function and structure.Further,electron microscopy images suggested that the mitochondria of renal tubular epithelial cells were swollen or even damaged.The Dynaminrelated protein 1 levels were increased in kidney tissues with chronic colitis.The respiratory chain function test showed that the isolated mitochondria from liver of colitis model present impaired ADP-stimulated respiration.Further,electron microscopy images suggested that the mitochondria of hepatocytes were swollen and disordered with increased collagen deposition in perisinusoidal area.Conclusions:(1)The meta-analysis showed that IBD was associated with endothelial dysfunction,increased arterial stiffness,and carotid intima-media thickness.(2)Abdominal aortic endothelial function was attenuated selectively in female mice with DSS-induced chronic colitis independent of ROS formation.DSS-induced colitis could increase liver and kidney vascular permeability.(3)DSS-induced colitis could increase liver and kidney vascular permeability by activating the AKT/e NOS pathway.Liver and kidney impairments in DSS-induced chronic colitis are associated with mitochondrial dysfunction.