Loss of the classical transient receptor potential 3 partially protects from hypoxia-induced pulmonary hypertension in mouse

Chronic hypoxia-induced pulmonary hypertension (CHPH) is a severe disease where patients suffer from exertional dyspnoea, chest pain, fatigue and dizziness. The raise in right ventricular systolic pressure (RVSP) causes a dilatation of the right ventricle, which can result in right heart insufficiency and malignant cardiac arrhythmia. CHPH is caused by the remodelling of the pulmonary arteries in hypoxic conditions at high altitude or due to lung diseases. It leads to increased pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR). In acute hypoxia the physiological mechanism of hypoxic pulmonary vasoconstriction (HPV) leads to a better perfusion of the superior ventilated areas. This process is physiological and fully reversible. The pathomechanism of the remodelling in CHPH is largely unknown. There is evidence that the increased proliferation of pulmonary arterial smooth muscle cells (PASMCs) result in reduced vessel diameter and increased contractility. Both are driven by intracellular calcium concentration. Classical transient receptor potential (TRPC) channels which belong to voltage-independent calcium channels consist of seven types with a largely unknown role in CHPH. They can form homo- and heterotetrameric cation channels which are selective for calcium and sodium. It was already shown that TRPC6 deficient mice lack HPV in response to acute hypoxia. Furthermore, TRPC1 deficient mice were characterized by a lower increase in RVSP, less remodelling and reduced PASMC proliferation after exposure to chronic hypoxia. This work focuses on the possible role of TRPC3 in HPV and CHPH. Acute and sustained hypoxic response was not altered by TRPC3 loss. However, TRPC3 deficient mice developed a milder increase of RVSP and a reduced remodelling of small pulmonary vessel after three weeks of hypoxia. In addition, gender specific differences were analysed but no correlation between gender, condition and genotype was observed.

In conclusion TRPC3 influences the development of CHPH and might be a potent target in CHPH therapy.