Upregulation of CXCL10/CXCR3 Axis Induced by Pulmonary Hemodynamic Stress Promotes Vascular Remodeling in Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND

Perivascular inflammation induced by abnormal hemodynamic stress is increasingly recognized as a key driver of secondary microvasculopathy in chronic thromboembolic pulmonary hypertension. Although circulating CXCL10 (C-X-C motif chemokine ligand 10) is elevated in chronic thromboembolic pulmonary hypertension and correlates with pulmonary hemodynamics, its mechanistic contribution to vascular remodeling remains unclear.

METHODS

Experiments were performed using pulmonary endarterectomy specimens from patients with chronic thromboembolic pulmonary hypertension and a left pulmonary artery ligation rat model.

RESULTS

In pulmonary endarterectomy specimens, CXCL10 was predominantly localized to CD68+ mannose receptor C-type 1+ macrophages, whereas CXCR3 (C-X-C motif chemokine receptor 3) was broadly expressed in the vascular wall and enriched in distal nonoccluded pulmonary arteries with increased mannose receptor C-type 1+ macrophage accumulation. In left pulmonary artery ligation rats, pulmonary hypertension and vascular remodeling were accompanied by perivascular accumulation of CXCL10+CXCR3+ mannose receptor C-type 1+ macrophages, increased plasma CXCL10, and upregulation of CXCL10 and CXCR3 in the right lung. CXCR3 expression was also increased in pulmonary arterial smooth muscle cells (PASMCs), and CXCL10 directly promoted proliferation of left pulmonary artery ligation-derived PASMCs in a CXCR3-dependent manner. In parallel, CXCL10 drove macrophages toward a proinflammatory, pro-proliferative secretory phenotype, and conditioned medium from macrophages enhanced PASMC proliferation. Pharmacological CXCR3 inhibition with AMG487 attenuated pulmonary hypertension, vascular remodeling, PASMC proliferation, and perivascular macrophage accumulation in both preventive and therapeutic settings. Similarly, cell type-specific CXCR3 knockdown in smooth muscle cells or macrophages ameliorated left pulmonary artery ligation-induced pulmonary hypertension, vascular remodeling, and associated perivascular inflammation.

CONCLUSIONS

The CXCL10/CXCR3 axis links hemodynamic stress to pulmonary vascular remodeling in chronic thromboembolic pulmonary hypertension by coordinating PASMC hyperproliferation and macrophage-driven inflammation, and may represent a therapeutic target.