Pulmonary arterial hypertension (PAH) is a serious, progressive disease that leads to increased blood pressure in the pulmonary arteries and ultimately right heart failure. Without treatment, half of the patients die within 3 years. Treatments improve quality of life and extend lifespan but do not cure the disease.
PAH is often caused by damage to endothelial cells in the pulmonary arteries, leading to changes in the blood vessels and increased blood pressure. Many factors contribute to this, with this thesis by Lysanne Jorna focusing on disruptions in the TGFβ and BMP signaling pathways, and mitochondrial dysfunction.
To explore this, the MCT-Flow rat model for PAH was further characterized, and a new method was developed to isolate endothelial cells from rat models of PAH and pulmonary hypertension (PH). This made it possible to study the molecular mechanisms behind the disease.
Most PAH-causing mutations disrupt the TGFβ and BMP signaling pathways. These pathways were tracked in endothelial cells during disease development in various rat models of PAH and PH, and the findings were placed in the context of current literature to promote the search for a treatment.
This thesis also investigates the effect of Sul-150, a mitochondrial-protective compound, in the MCT-Flow rat model for PAH. Sul-150 was found to inhibit PAH by protecting mitochondria and affecting specific receptors in the blood vessels. Long-term treatment with Sul-150 improved pulmonary artery structure and heart function in rats with PAH.
This thesis offers new insights for future PAH treatments, with a focus on improving endothelial cell function and addressing mitochondrial dysfunction.
