Specialized Pericyte Subtypes in the Pulmonary Capillary

Abstract

Pericytes (PCs) play crucial roles in capillary maturation, stability, and homeostasis. Impaired PC coverage and function are implicated in various diseases, including pulmonary arterial hypertension (PAH). Challenges investigating PC biology are largely due to the lack of a concise marker, resulting in difficulty distinguishing PCs from other mural cell populations, including smooth muscle cells (SMCs) and fibroblasts (FBs). Utilizing bioinformatic analysis and RNAscope, we identified HIG hypoxia-inducible domain family member 1B (Higd1b) as a unique and conserved gene marker for PCs and generated a novel knockin mouse line, Higd1b-CreERT2, which precisely labels PCs in the lung and heart. Human lung single-cell RNAseq suggested the presence of two HIGD1B+ PC subtypes with different functions. By lineage tracing pulmonary Higd1b+ cells exposed to hypoxia in vivo, we identified Type 1 PCs remained in the capillary network, while Type 2 PCs accumulated in the arterioles and coexpressed SMC markers and increased levels of Vimentin, associated with focal adhesion pathways. These results suggest that Type 1 PCs are specialized for supporting capillary EC homeostasis and quiescent, while Type 2 PCs are lineage active and located close to the border zone of the arterioles and capillaries, which may be motile and transition to SMC-like cells in hypoxia-induced pulmonary hypertension. The discovery of PC-type specialization in capillaries transforms our understanding of the structure, function and regulation of pulmonary capillary circulation and their contribution to vascular remodeling.