Inhibition of Vascular Endothelial Cadherin Cleavage Prevents Elastic Fiber Alterations and Atherosclerosis Induced by Intermittent Hypoxia in the Mouse Aorta.
Olfa HarkiSophie BouyonMarine SalléAlejandro Arco-HiervesEmeline LemariéAlexandra DemoryCarole ChiricaIsabelle VilgrainJean Louis PépinGilles FauryAnne Briançon-MarjolletPublished in: International journal of molecular sciences (2022)
Intermittent hypoxia (IH), the major feature of obstructive sleep apnea syndrome (OSAS), induces atherosclerosis and elastic fiber alterations. VE-cadherin cleavage is increased in OSAS patients and in an IH-cellular model. It is mediated by HIF-1 and Src-tyr-kinases pathways and results in endothelial hyperpermeability. Our aim was to determine whether blocking VE-cadherin cleavage in vivo could be an efficient strategy to inhibit deleterious IH-induced vascular remodeling, elastic fiber defects and atherogenesis. VE-cadherin regulation, aortic remodeling and atherosclerosis were studied in IH-exposed C57Bl/6J or ApoE-/-mice treated or not with Src-tyr-kinases inhibitors (Saracatinib/Pazopanib) or a HIF-1 inhibitor (Acriflavine). Human aortic endothelial cells were exposed to IH and treated with the same inhibitors. LDL and the monocytes transendothelium passage were measured. In vitro, IH increased transendothelium LDL and monocytes passage, and the tested inhibitors prevented these effects. In mice, IH decreased VE-cadherin expression and increased plasmatic sVE level, intima-media thickness, elastic fiber alterations and atherosclerosis, while the inhibitors prevented these in vivo effects. In vivo inhibition of HIF-1 and Src tyr kinase pathways were associated with the prevention of IH-induced elastic fiber/lamella degradation and atherogenesis, which suggests that VE-cadherin could be an important target to limit atherogenesis and progression of arterial stiffness in OSAS.
Keyphrases
- endothelial cells
- high glucose
- cell migration
- cell adhesion
- cardiovascular disease
- tyrosine kinase
- obstructive sleep apnea
- aortic valve
- newly diagnosed
- vascular endothelial growth factor
- end stage renal disease
- pulmonary artery
- dna binding
- machine learning
- ejection fraction
- type diabetes
- blood pressure
- diabetic rats
- high fat diet
- chronic kidney disease
- high intensity
- left ventricular
- peripheral blood
- high fat diet induced
- metabolic syndrome
- positive airway pressure
- immune response
- drug induced
- deep learning
- aortic dissection
- long non coding rna
- binding protein
- case report
- patient reported
- insulin resistance
- wild type