To allow for an efficient exchange of gases between the blood stream and the air, the lungs constitute the largest external surface area in a human body and, in turn, contain approximately half of the body's total endothelial cell surface. Given this extensive circulatory bed, realizing and recognizing the molecular diversity in healthy and diseased lungs is an important concept required for the development of targeted therapies and novel diagnostic methods of lung disease. Millions of people suffer from some form of lung disorder, which, if grouped together, would represent the third leading cause of death in the United States, affecting nearly 1 in 7 people. The development of novel targeted agents for diagnosing, imaging, and treatment of these diseases would greatly improve both health care and patient survival.
Vascular heterogeneity is a relatively new concept supported by a growing body of evidence generated over the past decades (1
). The antiquated view that blood vessels are a seemingly homogenous wall of almost identical endothelial cells has been replaced by the idea that blood vessels are, in fact, an intricate population of cells that differ among each other in organs and even within the same tissue. Such heterogeneity is already evident in the early stages of organ development, including the lung. Moreover, endothelial cells have an intimate connection with adjacent tissue, participating in organogenesis in an organ-specific manner. A lack of endothelial cells or a disruption in blood vessel formation interrupts lung development, and signals from the airways epithelial tissue are necessary for lung vasculogenesis and endothelial cell formation (5
). In the pancreas, an absence of endothelial cells prevents islet development and results in a halt of insulin production (7
) while, in the liver, they are important for tissue morphogenesis but their absence does not interfere with hepatocyte differentiation (8
). Hence, blood vessels are essential not only in supplying tissues and cells with oxygen and nutrients but also in modulating and shaping tissue and organ formation. Such close association between endothelium and tissue is likely to be maintained throughout adulthood and to play an important role in tissue homeostasis.
The existence of lung vascular heterogeneity has been proposed and has given rise to the identification of two distinct populations of endothelial cells: artery-derived and microvascular endothelial cells (9
). Interestingly, the current hypothesis for lung development proposes that the vasculature is formed by a combination of vasculogenesis (peripheral microvasculature) and angiogenesis (proximal macrovasculature) (reviewed in Reference 6
). This hypothesis supports the notion that the two different endothelial cell populations might have arisen as a result of these two embryonic processes. These cells display distinctive lectin-binding and E-cadherin expression profiles and respond differently to permeability-inducing drugs, reflecting some of the intricacies of the lung vascular bed (). Notably, endothelial cell heterogeneity does not seem to be limited to vascular beds from different organs and tissues; it can also be found within the same vessel branch or segment (9
). Other lung vascular ligands have also been identified on the basis ofntheir association with cancer metastasis: dipeptidyl peptidase (CD26) and Ca2+
-activated chloride channel (human CLCA-2 and mouse CLCA-1) (), both selectively expressed in the lung vasculature, serve as adhesion molecules for lung metastatic cancer cells (12
LIST OF SELECTED MOLECULAR LIGANDS PREFERENTIALLY EXPRESSED IN THE LUNG VASCULATURE IDENTIFIED THROUGH DIFFERENT METHODOLOGIES
Overall, more than 40 different cell types have been identified and characterized as components of human lungs and respiratory airways (14
) and as our understanding of the cellular diversity of the vasculature expands, we anticipate that other lung-derived endothelial cell populations will be recognized. In fact, the 2008 National Heart, Lung, and Blood Institute (NHLBI) workshop recommended further studies for the characterization of obscure and undefined cellular components of the lungs and the discovery of new and more efficient molecular markers for these various cellular types, including pulmonary vascular cells (14
). These recommendations, if accomplished, would represent important milestones in improving our knowledge of the diversity present in the airways' vascular bed and its implication in health and disease; however, these are not trivial tasks. To accomplish these goals, it is important to probe the surface of the vascular bed using functional assays that detect the availability and accessibility of receptors expressed on the cell surface to binding probes, without the limitations imposed by preconceived biases or assumptions about their nature. While different methodologies have been used toward this goal (), phage display stands out as a technique that is well-suited to assist in accomplishing such milestones.