Search

Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells, resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of patients with LAM develop pulmonary vascular remodeling and pulmonary hypertension. Little, however, is known regarding how LAM cells communicate with endothelial cells (ECs) to trigger vascular remodeling. In endstage LAM lung explants, we identified EC dysfunction characterized by increased EC proliferation and migration, defective angiogenesis, and dysmorphic endothelial tube network formation. To model LAM disease, we used an mTORC1 gain-offunction mouse model with a Tsc2 KO ([Tsc2.sup.KO]) specific to lung mesenchyme ([Tbx4.sup.LME-Cre] [Tsc2.sup.fl/fl]), similar to the mesenchymespecific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from mice exhibited marked transcriptomic changes despite an absence of morphological changes to the distal lung microvasculature. In contrast, 1-year-old [Tbx4.sup.LME-Cre] [Tsc2.sup.fl/fl] mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. Single-cell RNA- Seq of 1-year-old mouse lung cells identified paracrine ligands originating from [Tsc2.sup.KO] mesenchyme, which can signal through receptors in arterial ECs. These ECs had transcriptionally altered genes including those in pathways associated with blood vessel remodeling. The proposed pathophysiologic mesenchymal ligand-EC receptor crosstalk highlights the importance of an altered mesenchymal cell/EC axis in LAM and other hyperactive mTORC1-driven diseases. Since ECs in patients with LAM and in [Tbx4.sup.LME-Cre] [Tsc2.sup.fl/fl] mice did not harbor TSC2 mutations, our study demonstrates that constitutively active mTORC1 lung mesenchymal cells orchestrated dysfunctional EC responses that contributed to pulmonary vascular remodeling., Introduction Lymphangioleiomyomatosis (LAM) is a destructive lung disease characterized by diffuse parenchymal cystic airspace enlargement, airflow obstruction, and chylothorax from lymphatic involvement (1-6). In addition, some patients with LAM develop [...]