Interferon receptor gene dosage differentially regulates hypoxia-induced platelet activation and pulmonary hypertension in down syndrome

Trisomy 21 (T21) results in Down syndrome (DS), a condition associated with a high prevalence of pulmonary complications. Pulmonary hypertension (PH) is a significant comorbidity in individuals with T21.

Inflammation is a well-established driver of PH, and growing evidence implicates platelets as active contributors to inflammatory-mediated pulmonary vascular disease and PH. In T21, increased interferon (IFN) signaling resulting from an additional IFN receptor gene locus contributes to immune dysregulation, and interactions between platelet activation and IFN signaling may promote thromboinflammatory pathways associated with vascular disease.

To determine whether platelet activation is altered in T21, we first measured platelet activation by flow cytometry in individuals with T21 and age-matched controls. We then utilized the Dp16 mouse model of down syndrome to investigate IFN-dependent mechanisms.

WT, Dp16, and Dp162xIfnrs mice 7-9 weeks of age were exposed to 10% hypobaric hypoxia for 3 or 21 days or remained at Denver altitude. Platelet activation was measured by flow cytometry.

Lungs were collected to measure PF4 by ELISA and lung platelets by IHC. Vascular remodeling was measured by IHC staining of muscularized small vessels.