Hepatocyte growth factor may contribute to male protection against pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) presents as increased pressure in the pulmonary arteries (PA) leading to cardiac right ventricular (RV) failure and death. Pulmonary arterial (PA) remodeling characterized by enhanced proliferation of pulmonary arterial smooth muscle cells (PASMC) and fibroblasts (PAFB) underlies PAH. There are currently no cures and PAH mortality remains high. PAH has a striking female-predominant incidence - 4:1 ratio - indicating that males may have a protective factor. However, to date only a few sex-biased factors in PAH have been investigated.

Analyses were performed on a publicly available microarray dataset (GSE117261), comprising human lung tissues from PAH patients and healthy controls, as well as publicly available single-cell lung atlases of humans and mice. Lung tissue, plasma, PASMC and PAFB were collected from male and female PAH patients. Cell proliferation was assessed after recombinant HGF protein stimulation. PH was induced in male and female rats by monocrotaline (MCT). Lung-specific knockdown was performed by intratracheal siRNA instillation the first two weeks after MCT injection. PA and RV function were assessed by echocardiography, RV systolic pressure by catheterization, and PA remodeling by histology.

HGF was only upregulated in lungs of male PAH patients compared to male control lungs, but not in female PAH patients vs. female controls. Elevated plasma HGF correlated with favorable clinical characteristics only in male PAH patients. HGF is highly expressed in vascular SMC and FB in the lung and recombinant HGF inhibited PASMC and PAFB proliferation to a greater extent in cells isolated from male PAH patients compared to female. Lung HGF expression is increased to a higher extent and longer duration at early stage of PH in male rats in MCT model vs. female rats. Finally, knockdown of HGF in the lungs in early disease stage exacerbated PH in male rats characterized by higher mortality, worsened RV and PA function as well as enhanced PA medial thickening and adventitial fibrosis.

Lung HGF expression may be upregulated to counteract PAH disease progression by inhibiting proliferation of PASMC and PAFB. Elevated HGF in males might at least partially account for the lower incidence of male PAH patients.