Critical Role for Microvasculature in Airway Transplantation

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 DESCRIPTION (provided by applicant): While transplantation can be lifesaving, chronic rejection is frequently a major obstacle to long-term graft survival. Microvascular destruction is critical root-cause underlying this life-threatening process. Current immunosuppressive regimens do not sufficiently protect against microvascular injury and are not designed to help restore the transplant with healthy vascular cells. Promoting microvascular repair during rejection episodes is a promising new avenue for preventing chronic rejection in solid organ recipients. An understanding of the basic mechanisms explaining adaptive cell replacement is now needed to move the field forward. The proposed studies of this competitive renewal R01 grant are designed to explain two major processes: 1) how recipient cells are recruited to replace damaged transplant endothelial cells in microvessels and 2) how particular recipient cells, called Tie2 monocytes (TEMs), are also recruited to facilitate the angiogenic process. The project focuses on the role of the hypoxia-inducible factors (HIFs) that are the key transcription factors responsive to low tissue oxygen during rejection episodes when injured microvessels stop perfusing the transplanted tissues and fibrotic remodeling is promoted. Specific Aim 1 will determine how recipient cells, responding to HIF signals, differentially participate in transplant microvascular repair. The first subaim evaluates the contribution of endothelial-lineage cells and how a gain- and loss-of-function of HIF-1a or HIF-2a affects recipient cells investing into microvessels. The second subaim evaluates the contribution of non-endothelial cells, such as mesenchymal stem cells, and similarly evaluates how HIF-1a expression affects their ability to incorporate into damaged vessels. Specific Aim 2 will determine the role of HIF-1a and HIF-2a on TEM migration and angiogenesis. Four subaims evaluate the role of HIF isoforms in a series of in vivo and in vitro studies that address whether upregulating HIF production in TEMs promotes angiogenesis via the production of prostaglandin E2.