Understanding and Engineering the Pulmonary Vasculature.

Blood vessels play essential roles in regulating embryonic organogenesis and adult tissue homeostasis. The inner lining of blood vessels is covered by vascular endothelial cells, which exhibit tissue-specific phenotypes in term of their molecular signature, morphology, and function. The pulmonary microvascular endothelium is continuous and non-fenestrae to ensure stringent barrier function while allowing efficient gas exchange across the alveoli-capillary interface. During respiratory injury repair, pulmonary microvascular endothelial cells secrete unique angiocrine factors and actively participate in the molecular and cellular events mediating alveolar regeneration. Advances in stem cell and organoid engineering are offering new ways to produce vascularized lung tissue models to investigate vascular-parenchymal interactions during lung organogenesis and pathogenesis. Further, technology developments in 3D biomaterial fabrication are enabling construction of vascularized tissues and microdevices with organotypic features at high resolution to recapitulate the air-blood interface. In parallel, whole-lung decellularization produces biomaterial scaffolds with naturally occurring, acellular vascular bed with preserved tissue architecture and complexity. Emerging efforts in combining cells with synthetic or natural biomaterials open vast opportunities for engineering the organotypic pulmonary vasculature to address current limitations in regenerating and repairing damaged lungs and pave the way towards next-generation therapies for pulmonary vascular diseases.