Specialized Pulmonary Vascular Cells in Development and Disease

Abstract

Endothelial cells (ECs) develop organ-specific gene expression and function in response to signals from the surrounding tissue. In turn, ECs can affect organ development and morphogenesis and promote or hinder disease response. In the lung, ECs play an essential role in gas exchange with the external environment, requiring both a close physical connection and a strong axis of communication with alveolar epithelial cells. A complete picture of the composition of the pulmonary endothelium is therefore critical for a full understanding of development, maintenance, and repair of the gas exchange interface. Defining the factors that control lung-specific EC specification, establish EC heterogeneity within the lung, and promote the differing contributions of EC subtypes to development, health, and disease will facilitate the development of much-needed regenerative therapies. This includes targeting therapeutics directly to ECs, developing pluripotent or primary cell-derived ECs to replace damaged or diseased vasculature, and vascularizing engineered tissues for transplant.

Keywords: lung development; lung progenitors; lung regeneration; lung stem cells; pulmonary endothelium; regenerative medicine.

Figure 1.. Identification of specialized pulmonary endothelial cells (ECs) in development, homeostasis, and disease.

(A) Capillary type 1 ECs (CAP1) and capillary type 2 ECs (CAP2) in the mouse and human lung differ in gene expression, abundance, and localization. CAP1s specifically express Plvap, Aplnr, and Gpihpb1. Mouse CAP2s specifically express Car4 and Apln, while mouse and human CAP2s express EDNRB. CAP2 ECs are located on the “thin side” of the alveolar wall in close contact with alveolar type 1 (AT1) epithelial cells. CAP1s are more abundant, while CAP2s make up approximately 15% of the capillary endothelium. (B) CAP2s also differ from CAP1s in size, spanning multiple vessel segments. (C) CAP1 ECs possess the ability to proliferate during development and regeneration, but rarely do so at homeostasis. Lineage tracing using CAP1-specific Cre mouse lines has shown that CAP1s can generate CAP2s. CAP2s arise during late embryonic and early postnatal life in the mouse, a process that requires VEGF signaling. AF1, alveolar fibroblast type 1; AF2, alveolar fibroblast type 2; AT1, alveolar type 1 epithelial cell; AT2, alveolar type 2 epithelial cell; CAP1, capillary endothelial type 1; CAP2, capillary endothelial type 2; RBC, red blood cell. Created with biorender.com.

Figure 2.. Effects of viral infection and inflammation on the pulmonary endothelium.

After viral infection of the healthy lung (A), an influx of immune cells creates inflammation that is necessary for viral clearance. (B) Inflammation is a “double-edged sword,” as it also causes tissue damage. ECs respond to inflammation and structural damage by proliferating, which is required to create new vessels but may also contribute to pathology. Different EC subtypes respond differently to infection, which impacts their gene expression and signaling. Created with biorender.com.