Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities

Abstract

Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34 ؉ CD133 ؉ proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 ␣ (HIF-1␣). Here, CD34 ؉ CD133 ؉ progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 ␣ (SDF-1␣) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process. (Blood. 2011;117(13):3485-3493) IntroductionPulmonary arterial hypertension (PAH) is a vasculopathy of the pulmonary circulation characterized by arterial obliteration secondary to unchecked pathologic angiogenic processes. 1-3 An abundance of studies over the past decade provide evidence for the paradigm of lifelong interdependence between angiogenesis and hematopoiesis. [4][5][6] The concept of a common hematopoieticendothelial stem cell, that is, hemangioblast, with bidirectional, reversible gene transcription and persistence is well established in developmental biology. 7 In postnatal life to adulthood, hemangioblasts are readily identifiable in the bone marrow by the CD133-selective expression on a small subpopulation of CD34-positive hematopoietic stem cells. 8 Hemangioblasts give rise to all blood cellular components, but whether these cells give rise to endothelium during postnatal neovascularization is uncertain. 9,10 In contrast, studies clearly substantiate that CD34 ϩ CD133 ϩ progenitors are vital contributors to angiogenesis via proangiogenic effects on endothelial cells in vessels. [11][12][13][14][15][16][17][18] Our and other studies identify that CD34 ϩ CD133 ϩ progenitors are present at higher than normal levels in the circulation of PAH patients and are more proliferative than circulating progenitors of healthy controls. 19,20 The relationship of numbers of circulating CD34 ϩ CD133 ϩ cells to severity of PAH suggest that these cells may promote the angioproliferative vascular remodeling. 20 However, whether the source ...

Involvement of endothelial progenitor cells in the formation of plexiform lesions in broiler chickens: possible role of local immune/inflammatory response

“…In the present study, we found a strong expression of HGF in PLs, consistent with the studies on human PAH (Farha et al, 2011). As an important factor responsible for vascular repair, HGF has been shown to enhance EPC function and improve EPC transplant efficiency in experimentally induced arterial injury (Song et al, 2009;Yu et al, 2015).…”

Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target

“…However, as in healthy controls, there is a negative correlation between the two that is consistent with a reduction in hepcidin production as erythropoietic demand for iron increases [5,55]. Iron deficiency or anaemia may also drive increases in other HIF-inducible factors, including the myeloidactivating factors stromal-derived factor-1a, stem cell factor and hepatocyte growth factor [55].…”

“…Iron deficiency or anaemia may also drive increases in other HIF-inducible factors, including the myeloidactivating factors stromal-derived factor-1a, stem cell factor and hepatocyte growth factor [55]. This might contribute to myeloproliferative processes and recruitment of pro-angiogenic progenitor (CD34+ CD133+) cells to the pulmonary vasculature in PAH patients [55]. Interestingly, myeloid abnormalities were also demonstrated in unaffected relations of HPAH patients, suggesting that HIF-inducible factors and myeloid abnormalities may have a role in the pathology of PAH prior to the clinical manifestation of the disease.…”

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

“…Several independent investigations have described a mobilization of BM-derived cells during pulmonary hypertension. 2 Not only cells expressing c-kit are mobilized from BM in the circulation in response to hypoxia, but they are also found in the remodeled lung vessel wall in PAH (Figure 3 and Hayashida et al, 7 Davie et al, 8 Farha et al, 12 Spees et al, 24 and Sata et al 31 ). Activation of c-kit was reported as necessary for mobilization of reparative BM progenitor cells 32 and for the remodeling of blood vessels from these progenitor cells.…”

“…9 Other observations have also identified an association between PAH and BMrelated hematologic disorders 10 : in proliferative disorders of the hematopoietic stem cells such as myeloproliferative cancers, there is an unexplained high incidence of PAH. PAH is now a recognized complication of BM transplantation for leukemia, 11 chronic myeloproliferative disorders, 12 or in the treatment of malignant infantile osteopetrosis. 13 On the other hand, serotonin (5-hydroxytryptamine ) is associated with the pathogenesis of PAH.…”