Endothelial Cell Heterogeneity in the Pulmonary Circulation

The pulmonary circulation is unique among vascular beds in that it is the only organ system to receive 100 percent of the cardiac output through a low-resistance, low-pressure circuit. Within this unique circulation, different anatomical compartments can be distinguished between the macro- and microvascular segments and between the bronchial and pulmonary circulations. Whereas the bronchial circulation delivers oxygenated arterial blood from the left ventricle to support the bronchial and large airway tissues, the pulmonary circulation delivers mixed venous blood from the right ventricle through the pulmonary artery to the alveolar septal network for gas exchange. This oxygenated blood is then returned through pulmonary venules and veins to the left atria and ventricle for delivery to the systemic circulation. Considerable structural and functional diversity has been described among endothelial cells in these various compartments within the pulmonary circulation.

Heterogeneity among pulmonary endothelial cells of large vessels and capillaries is now well recognized both morphologically and physiologically. Morphologically, cells in larger vessels under laminar shear rates are elongated and aligned in the direction of flow, whereas those in the capillaries are not aligned in the direction of flow. Because of their exposure to different magnitude and types of shear stress, part of the heterogeneity may be attributed to adaptation to blood flow, suggesting that lung macro- and microvascular endothelial cells differ in their interpretation of and response to mechanical forces.

In addition, physiologic heterogeneity has also been demonstrated by various groups who have examined segment-specific permeability features of lung endothelium. Early work in this area illustrated most of the baseline fluid flux occurred across capillary (46%) and venous segments (38%). Segment measurements rely on subtracting arterial or venule permeability from total filtration. To ascertain these values, high airway pressure is typically used to collapse alveolar capillaries segments, stopping continuity of blood flow. Although it is unlikely that flow is completely abolished through corner vessels, these findings are broadly reflective of segment-specific responses. In fact, a series of subsequent studies have borne out these initial results, demonstrating pulmonary artery/arteriole segments account for 16 to 24 percent of basal water permeability, while capillary (36 to 50%) and venule/vein (33 to 46%) segments each account for the bulk of the circulation's total basal water flux [2]. Although this work illustrates that capillary endothelial cells account for a substantial portion of basal permeability, they do not suggest capillary endothelial cells are highly water and protein permeable. Indeed, when standardized to relative surface area, it becomes immediately apparent that the capillary endothelial cell barrier is 58 and 26-fold more restrictive to flux than either the pre- or post-capillary barrier segments, respectively.

It is of particular importance that precapillary (artery/arteriole), capillary, and postcapillary (venule/vein) vascular segments are differentially targeted by physiological and pathophysiological stimuli. In the case of increased airway pressure, which is relevant to ventilator-induced lung injury, increased permeability occurs primarily across capillary segments [2]. Similar results were observed by West and colleagues [3] in capillaries subjected to high vascular pressure that illustrated endothelial cell "stress failure" by electron microscopy. In the case of oxidant-mediated injury, which is relevant to lung transplantation, and in the case of hydrogen peroxide- and xanthine oxidase-induced vascular injury, postcapillary venule/vein segments are the preferential targets [4]. Increased permeability arising from either segment can eventually cause frank pulmonary edema if the rate of fluid accumulation exceeds the rate of reabsorption and clearance through the lymphatics. Thus, it is critical to understand the basis for such site-specific heterogeneity.

In 1997 our group demonstrated that the plant alkaloid thapsigargin activates store operated calcium entry and increases lung endothelial cell permeability. These findings indicate that calcium entry across the cell membrane is sufficient to produce intercellular gaps that form a paracellular pathway for water and protein transudation, similar to earlier work using Gq agonists such as histamine, thrombin, and substance P. However, upon close inspection of the pulmonary circulation, we resolved that not all segments were equally effected by thapsigargin [5]. Indeed, this agonist only induced intercellular gaps in arteries and veins larger than approximately 75 to 100 mm (Figure 1A). These findings suggested that rises in cytosolic calcium, through store-operated calcium entry channels, selectively targeted large vessel segments, prompting a more sophisticated evaluation of mechanisms of endothelial cell heterogeneity.

Evidence that thapsigargin increases permeability in pulmonary artery and vein segments, but not in capillary segments, suggests that neither drug concentration nor site-specific "environmental" influences underlie the heterogeneity in response. Another possible explanation is that endothelial cells within the large and small blood vessels arise from different progenitor cells and become imprinted by their unique (site-specific) environments to achieve a differentiated phenotype. As these endothelia are genetically identical, multiple epigenetic (i.e., beyond the gene sequence) mechanisms likely account for the stable modifications in cell phenotype, including methylation of promoter sequences that inhibit gene expression, and acetylation of histone proteins that control access of transcription factors to promoter sequences [8].

Lung developmental studies also provide evidence that the endothelia in particular segments are phenotypically distinct. DeMello and coworkers [6] mapped the origin of lung blood vessels using a Mercox casting technique (Figure 1B). Their findings indicated the rudimentary pulmonary circulation was first apparent in the early pseudoglandular phase of lung development. However, the circulation was incomplete, and only large blood vessels could be resolved to be intact with the right ventricle (Figure 1B, left panel). Parallel studies revealed simultaneous development of blood islands with immature capillaries, apparently not contiguous with the pulmonary artery or vein. Late in the pseudoglan-dular phase of lung development, an intact circulation was observed with large vessel segments contiguous with capillaries (Figure 1B, right panel). These authors suggested that large vessels arise from angiogenesis, the sequential branching of new blood vessels from existing ones, whereas capillaries (alveolar septal network) arise by vasculogenesis, the coalescence of blood lakes made up of mesenchymally derived cells. They further suggested at mid-gestation these different segments fuse to form a continuous vascular network. Although certain aspects of these findings have been debated, it appears clear that large and small blood vessel endothelium is derived from different mesenchymal cells that interact with site-specific environmental cues and are stably imprinted to become differentiated phenotypes.

If this idea is correct, then macro- and microvascular cells should share global endothelial cell behaviors but pos-

Control Thapsigargin-perfused pulmonary vessels

Vein Vein Artery Microcirculation
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