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SummaryThe pulmonary endothelium plays a significant role in the pathobiology of Primary Pulmonary Hypertension. A number of diseases, related by a history of vascular injury, are associated with increased numbers of circulating endothelial cells (CECs). We hypothesized that patients with pulmonary hypertension would also have an increased number of circulating endothelial cells due to the high pressures and increased shear stress present within the pulmonary vasculature. We isolated the CECs from 14 patients with pulmonary hypertension, (5 primary and 11 secondary) and compared them to the cells from 12 normal controls. There was a significant increase in the number of CECs in peripheral blood in patients with both PPH and secondary pulmonary hypertension (SPH) when compared to normal volunteers (33.1 +/- 1.9 {PPH} and 27.2 +/- 6.9 {SPH} vs. 3.5 +/- 1.3 {controls}, p < 0.001). The number of circulating endothelial cells in the patient’s peripheral blood correlated significantly with the systolic, diastolic and mean pulmonary artery pressures of the individual. Approximately 50% of the CECs from patients with pulmonary hypertension expressed CD36, a marker of microvascular origin and 25% expressed E-selectin, a marker of endothelial cell activation. Although the origin of the CECs in patients with PH requires further investigation, one possible source is the pulmonary vasculature, and in patients with plexogenic pulmonary hypertension, the plexiform lesions. CECs may provide a non-invasive mean of accessing cells important to the pathobiology of severe pulmonary hypertension.

This work was supported by National Institute of Health grants 1RO1 HL60195-01 and 1RO1 HL60913-01, the American Heart Association, Desert Mountain Division Grant HL-00513532, and the Shirley Kiner Witham Memorial Pulmonary Hypertension Research Fund. Research regarding understanding of the molecular mechanisms of pulmonary hypertension (PH) has experienced great progress in the last 3 yrs. Efforts to map the genetic susceptibility of familial primary pulmonary hypertension (FPPH) succeeded in localizing the gene site to the region 2q32-33, or so-called PPH1 gene site, which encompasses ∼3 centimorgan 1, 2. This finding raised the hope that important information could be generated since the prevailing concepts concerning the pathogenesis of primary pulmonary hypertension (PPH) have revolved around the pathophysiological roles of cellular components of vascular remodelling and abnormalities of pulmonary vascular tone control. The importance of the alterations of pulmonary vascular morphology was felt, by some, to be minimal, since they were interpreted to occur late in the disease process. Clearly, concepts were borrowed from hypoxic pulmonary vasoconstriction, yet severe PH is an irreversible disease with a magnitude of pulmonary hypertension not usually seen in acute or chronic hypoxia. Shortly after the FPPH locus had been announced, plexiform lesions in PPH were characterized to represent a tumour-like proliferation of a monoclonal population of endothelial cells, indicating that the endothelial cells arose from a selective growth of a single cell, whereas, in secondary PH, endothelial cells in plexiform lesions were polyclonal 3, 4. This finding in turn pointed towards mutational events, such as involving activation of growth-inducing kinase receptors or loss of tumour suppressor genes, as being responsible for the clonal expansion of endothelial cells in PPH 5. Recently, germline mutations in the bone morphogenetic protein receptor II (BMPR-II) (coded within the 2q32-33 region of the PPH1 gene site) were identified …