Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by a fibrotic thrombus persisting and obliterating the lumen of pulmonary arteries; its pathogenesis remains poorly defined. This study investigates a potential contribution for progenitor cell types in the development of vascular obliteration and remodeling in CTEPH patients. Endarterectomized tissue from patients undergoing pulmonary thromboendarterectomy was collected and examined for the structure and cellular composition. Our data show an organized fibrin network structure in unresolved thromboemboli and intimal remodeling in vascular wall tissues, characterized by smooth muscle alpha-actin (SM-alphaA)-positive cell proliferation in proximal regions (adjacent to thromboemboli) and neoangiogenesis/recanalization in distal regions (downstream from thromboemboli). Cells that are positively stained with CD34 and fetal liver kinase-1 (Flk-1) (CD34(+)Flk-1(+)) were identified in both the proximal and distal vascular tissues; a subpopulation of CD34(+)Flk-1(+)CD133(+) cells were further identified by immunostaining. Triple-positive cells are indicative of a population of putative endothelial progenitor cells or potential colony-forming units of endothelial cells. In addition, inflammatory cells (CD45(+)) and collagen-secreting cells (procollagen-1(+)) were detected in the proximal vascular wall. Some of the CD34(+) cells in CTEPH cells isolated from proximal regions were also positive for SM-alphaA. Our data indicate that putative progenitor cell types are present in the neointima of occluded vessels of CTEPH patients. It is possible that the microenvironment provided by thromboemboli may promote these putative progenitor cells to differentiate and enhance intimal remodeling.

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Sacks RS, Firth AL, Remillard CV, Agange N, Yau J, Ko EA, Yuan JX. Thrombin-mediated increases in cytosolic [Ca 2ϩ ] involve different mechanisms in human pulmonary artery smooth muscle and endothelial cells. Am J Physiol Lung Cell Mol Physiol 295: L1048 -L1055, 2008. First published October 3, 2008 doi:10.1152/ajplung.90259.2008.-Thrombin is a procoagulant inflammatory agonist that can disrupt the endothelium-lumen barrier in the lung by causing contraction of endothelial cells and promote pulmonary cell proliferation. Both contraction and proliferation require increases in cytosolic Ca 2ϩ concentration ([Ca 2ϩ ]cyt). In this study, we compared the effect of thrombin on Ca 2ϩ signaling in human pulmonary artery smooth muscle (PASMC) and endothelial (PAEC) cells. Thrombin increased the [Ca 2ϩ ]cyt in both cell types; however, the transient response was significantly higher and recovered quicker in the PASMC, suggesting different mechanisms may contribute to thrombin-mediated increases in [Ca 2ϩ ]cyt in these cell types. Depletion of intracellular stores with cyclopiazonic acid (CPA) in the absence of extracellular Ca 2ϩ induced calcium transients representative of those observed in response to thrombin in both cell types. Interestingly, CPA pretreatment significantly attenuated thrombin-induced Ca 2ϩ release in PASMC; this attenuation was not apparent in PAEC, indicating that a PAEC-specific mechanism was targeted by thrombin. Treatment with a combination of CPA, caffeine, and ryanodine also failed to abolish the thrombin-induced Ca 2ϩ transient in PAEC. Notably, thrombin-induced receptor-mediated calcium influx was still observed in PASMC after CPA pretreatment in the presence of extracellular Ca 2ϩ . Ca 2ϩ oscillations were triggered by thrombin in PASMC resulting from a balance of extracellular Ca 2ϩ influx and Ca 2ϩ reuptake by the sarcoplasmic reticulum. The data show that thrombin induces increases in intracellular calcium in PASMC and PAEC with a distinct CPA-, caffeine-, and ryanodineinsensitive release existing only in PAEC. Furthermore, a dynamic balance between Ca 2ϩ influx, intracellular Ca 2ϩ release, and reuptake underlie the Ca 2ϩ transients evoked by thrombin in some PASMC. Understanding of such mechanisms will provide an important insight into thrombin-mediated vascular injury during hypertension. sarcoplasmic and endoplasmic reticulum; Ca 2ϩ store THROMBIN, A MAJOR EFFECTOR PROTEASE of the coagulation cascade, is best known for its role in the conversion of fibrinogen into fibrin. Thrombin can operate as an inflammatory agent by stimulating endothelial cells (EC) to produce and/or secrete chemotactic factors by promoting monocyte recruitment and by increasing endothelial permeability (8, 9). At the same time, thrombin regulates the inflammation processes by blocking aggregation of platelets, adhesion of monocytes to endothelium, and by releasing nitric oxide (NO) from EC (35). In the lung, thrombin has a number of effects not limited to coagulation, which may play significant roles in ...

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