In the SETD2 specific knockout mouse model, the SMC lacking SETD2 protects mice from hypoxic PAH and significantly reduces related pathological parameters, such as the right ventricular systolic pressure (RVSP), the right ventricular/left ventricular plus septum [RV/(LV + S)] weight ratio, and the pulmonary median width. Here, SETD2 is linked to pulmonary arterial hypertension.