# BMP9 knockout impairs pulmonary vessel muscularisation and confers aberrant tamoxifen sensitivity

## TL;DR

Deleting the BMP9 gene in mice leads to reduced muscle in lung blood vessels and unexpected sensitivity to tamoxifen, affecting disease models.

## Contribution

The study identifies COLQ and ITGA6 as novel genes affected by BMP9 knockout and reveals tamoxifen sensitivity in Bmp9 KO mice.

## Key findings

- BMP9 knockout mice show reduced pulmonary vascular smooth muscle cell coverage.
- COLQ and ITGA6 are differentially regulated in Bmp9 KO mice and human PAH datasets.
- Tamoxifen-treated Bmp9 KO mice phenocopy dKO mice with cardiomegaly and pulmonary changes.

## Abstract

Deleterious mutations in the GDF2 gene, encoding BMP9, are causative of pulmonary arterial hypertension and hereditary haemorrhagic telangiectasia. Paradoxically, BMP9 germ-line knockout (Gdf2−/−; Bmp9 KO) and double Bmp9 KO/conditional Bmp10 cKO (dKO) mice exhibit an attenuated response to PAH-inducing stimuli. We asked whether this contradiction is due to the pathological, physiological, or genetic consequences of BMP9 knockout. In Bmp9 KO mice we observed reduced pulmonary vascular smooth muscle cell (SMC) coverage and using RNA-seq analysis of Bmp9 KO mouse lungs identified two novel genes, COLQ and ITGA6, which were differentially regulated in a human PAH RNA-seq dataset. In order to study BMP10 loss, postnatal tamoxifen treatment was required to induce Bmp10 cKO. As previously reported, in dKO mice we observed cardiomegaly and splenomegaly, as well as hyperplasia and hemosiderosis in the pulmonary vasculature. Surprisingly, tamoxifen treated Bmp9 KO control mice phenocopied these pathological changes in dKO mice and downregulated SMC marker gene transcription. Loss of BMP10 is not critical for severe tissue remodelling in the lung, heart, and spleen, rather Bmp9 KO mice appear sensitive to tamoxifen and BMP9 loss is the primary cause of mild vessel remodelling due to a basal reduction of smooth muscle cell coverage. This study suggests that interaction of the BMP pathway with tamoxifen needs to be carefully considered when studying Bmp9 KO mice and urges caution in the context of tamoxifen use when studying cardiovascular and pulmonary disease models.

The online version contains supplementary material available at 10.1007/s10456-025-10017-5.