Background Pulmonary arterial hypertension (PAH) is a rare disease whose etiopathogenesis is poorly understood, and existing treatments are neither curative nor sufficient for stopping disease progression . PAH is one of the major complications of connective tissue diseases, and 7–15% of patients with systemic sclerosis (SSc) develop PAH . Mice deficient for the leukocytic receptor P-selectin glycoprotein ligand-1 (PSGL-1-/-) spontaneously develop a SSc-like autoimmune syndrome with ageing .
Objectives To check whether PSGL-/- mice may develop PAH and which mechanisms might be implicated in the initiation and progression of the disease.
Methods Vascular remodeling was assessed by immunohistochemistry on lung sections of WT and PSGL-1-/- C57BL/6 mice. Doppler pulse echochardiography was used to evaluate pulmonary artery flow acceleration time/ ejection time (TPV/ET) ratio. Isolated pulmonary artery rings were incubated with KCL, serotonin or acetylcholine and responses were registrated with a wire myograph coupled to an isometric force transducer. Angiotensin II lung concentration was quantified by ELISA. ACE, ACE2, AT1R and AT2R expression was evaluated by western blot. Expression levels of the NO-sensing probe DAR-4M AM and IFN-γ were measured by flow cytometry.
Results PSGL-1-/- mice presented vascular remodeling of distal lung blood vessels. Aged PSGL-1-/- females showed reduced flow TPV/ET ratio in the pulmonary artery and RV remodeling, indicating PAH. Moreover, pulmonary arterial rings from aged PSGL-1-/- females presented increased vasoconstriction response to KCL and reduced vasodilation response to acetylcholine. Importantly, NO production by lung EC was reduced in aged PSGL-1-/- females. Expression of AT2R was reduced in lungs of PSGL-1-/- females from a young age. With ageing, the levels of angiotensin II and the percentages of IFN-γ-producing interstitial macrophages, T and B lymphocytes were increased in PSGL-1-/- females.
Conclusions Together, these studies implicate leukocyte-endothelium interactions for the maintenance of vascular homeostasis and protection against PAH in PSGL-1 deficient female mice.
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Acknowledgements We want to thank Ana Vanesa Alonso and Lorena Flores from the Unit of Advanced Imaging of the CNIC for their crucial support in echocardiography performance.
Disclosure of Interest None declared