EDIL3 regulates pulmonary artery smooth muscle cell proliferation and migration via integrin αVβ3/ERK1/2 axis in pulmonary hypertension.

The abnormal expression of matricellular proteins involved in pulmonary vascular remodelling can accelerate the development of pulmonary hypertension (PH). Epidermal growth factor-like repeats and discoidin I-like domains 3 (EDIL3) is a matrix protein associated with the onset and progression of various diseases, yet its role in PH remains unexamined. This research aims to assess the expression of EDIL3 in PH and to investigate its underlying mechanisms in the condition. Our results indicated that EDIL3 levels are elevated in patients with idiopathic pulmonary arterial hypertension (iPAH), as well as in hypoxia-treated pulmonary artery smooth muscle cells (PASMCs) compared to normoxia-treated controls. Additionally, a mouse model of PH induced by SU5416 along with hypoxia (Su/Hx) also expressed elevated EDIL3 levels. We discovered that EDIL3 knockdown diminished the proliferation and migration of PASMCs. Mechanically, we identified an interaction between EDIL3 and integrin αVβ3. The regulation of PASMCs proliferation by EDIL3 was disrupted by cilengitide, an RGD pentapeptide that serves as a potent and selective inhibitor of integrin αVβ3. Furthermore, recombinant EDIL3 significantly increased the level of p-ERK1/2, an effect that was blocked by cilengitide, while p-p38 and p-JNK levels remained unchanged. In summary, our study introduces a novel therapeutic strategy for treating PAH and highlights a new serum biomarker for its diagnosis.