Pulmonary Vascular Regeneration via Venous Endothelial Progenitors

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Project Summary Respiratory viral infections represent a major risk factor for the development of acute respiratory distress syndrome. Moreover, severe influenza injury can result in ineffective repair and persistent loss of pulmonary function. The lung endothelium, especially the microvasculature, is damaged due to the robust inflammatory response from viral infections, but the mechanisms of pulmonary endothelium regeneration after severe influenza injury are not completely elucidated despite the vasculature’s central importance in gas exchange. This proposal aims to answer fundamental questions about pulmonary vascular regeneration regarding the origin of vascular progenitor(s) and the mechanisms driving endothelial repair in response to influenza injury. We recently demonstrated that COUP-TFII, a vein-specifying transcription factor enriched in proliferating endothelial cells, is necessary for lung regeneration. The venous endothelium is increasingly recognized as a vascular progenitor population for endothelial regeneration in various organs in zebrafish and mice, suggesting that pulmonary veins / venules may similarly harbor potent progenitor cells. In my own preliminary data, I observed that venous endothelial cell clones are highly proliferative and can span into the microvasculature. Aim 1 of this proposal will utilize clonal lineage tracing and orthotopic transplantation techniques to determine if the venous endothelium harbors potent progenitor and proliferative potential during lung regeneration. The second focus of this proposal is to elucidate the mechanisms and interactions that are required for endothelial proliferation. Along with expression of venous markers, proliferating endothelial cells secrete C-C Motif Chemokine Ligand 2 (CCL2), a chemokine involved in mediating the inflammatory response during injury. The CCL2-CCR2 signaling axis promotes inflammatory angiogenesis in mice through recruitment of monocyte derived inflammatory macrophages, indicating a role for endothelial-specific release of CCL2 during tissue repair. Therefore, Aim 2 will employ conditional, temporal deletion of CCL2 in endothelial cells and clodronate-liposome mediated depletion of macrophages to investigate if loss of endothelial-derived CCL2 impacts endothelial proliferation and consequent angiogenic repair. This proposal will address the central hypothesis that a pulmonary endothelial progenitor population present in the preexisting venous endothelium secretes CCL2 to recruit interstitial monocytes to provide an angiogenic niche. Completion of this project will validate the venous endothelium as an important contributor to pulmonary regeneration and will also facilitate identification of specific paracrine / immune pathways that could allow for precise regulation and preservation of the beneficial immune response.