Figure 11. Schematic of endothelial cell (EC) populations contributing to microvascular repair.

At baseline (day 0), there are two main alveolar groups of capillary ECs: larger apelin-positive aerocytes (aCap) ECs, termed aerocytes, that play a key structural role in forming the air-blood barrier; and smaller apelin receptor-expressing general capillary (gCap) ECs, which are found in the thicker regions at the corners of the alveoli. After diphtheria toxin (DT)-induced EC ablation, there is a marked depletion of both EC populations and the appearance of novel transitional and transient populations. At day 3, there is the appearance of stem-like gCap ECs that paradoxically express apelin, but not its receptor, and are characterized by various stem and progenitor cell markers but show no evidence of proliferation. By day 5, these transition to ECs expressing Aplnr which have a strong proliferative phenotype, as evidenced by Forkhead box M1 (Foxm1) and Mki67 expression, and then rapidly replenish depleted EC pools, including aCap ECs, by day 7. This transition is orchestrated by the interaction of apelin with its receptor as a critical mechanism in lung microvascular regeneration after EC injury. AT1, alveolar type –1 epithelial cell; AT2, alveolar type-2 epithelial cell; APLNR, apelin receptor; ANGPT2, angipoietin 2; PROCR, protein C receptor.

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