Abstract
Despite the widespread use of CD34-family sialomucins (CD34, podocalyxin and endoglycan) as vascular endothelial cell markers, there is remarkably little known of their vascular function. Podocalyxin (gene name Podxl), in particular, has been difficult to study in adult vasculature as germ-line deletion of podocalyxin in mice leads to kidney malformations and perinatal death. We generated mice that conditionally delete podocalyxin in vascular endothelial cells (Podxl ΔEC mice) to study the homeostatic role of podocalyxin in adult mouse vessels. Although Podxl ΔEC adult mice are viable, their lungs display increased lung volume and changes to the matrix composition. Intriguingly, this was associated with increased basal and inflammation-induced pulmonary vascular permeability. To further investigate the etiology of these defects, we isolated mouse pulmonary endothelial cells. Podxl ΔEC endothelial cells display mildly enhanced static adhesion to fibronectin but spread normally when plated on fibronectin-coated transwells. In contrast, Podxl ΔEC endothelial cells exhibit a severely impaired ability to spread on laminin and, to a lesser extent, collagen I coated transwells. The data suggest that, in endothelial cells, podocalyxin plays a previously unrecognized role in maintaining vascular integrity, likely through orchestrating interactions with extracellular matrix components and basement membranes, and that this influences downstream epithelial architecture.
Highlights
Lung development is a highly regulated process requiring tight coordination between airway morphogenesis/alveolarization and vasculogenesis/angiogenesis [1,2]
In the kidney, where the bulk of podocalyxin expression is in the glomerular epithelial cells, we could not detect a noticeable difference in mRNA levels (Fig. 1C)
By immunohistology it is clear that podocalyxin is ablated in the endothelial cells found at the centre of the glomerulus and in large vessels (Fig. 2D), while the residual podocalyxin is expressed in the kidney podocytes of the glomeruli and the ductal cells
Summary
Lung development is a highly regulated process requiring tight coordination between airway morphogenesis/alveolarization and vasculogenesis/angiogenesis [1,2]. Lung alveolar function requires the development of a tight alveolar-capillary complex to facilitate pulmonary gas exchange. The maintenance of vessel patency by cell-cell and cell-matrix interactions is a critical factor in regulating both vascular permeability and proper airway function. Abnormal vessel growth and vascular dysfunction contribute to a number of pediatric and adult lung pathologies, including bronchopulmonary dysplasia and chronic obstructive pulmonary disease [5,6]. The loss of genes regulating vessel development and patency or the administration of antiangiogenic drugs can lead to defects in alveolarization and lung structure [7,8,9]. Lung vessel patency and the regulation of permeability are closely linked to lung structure and function
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