The rare association of pulmonary hypertension and myeloproliferative syndromes (MPS) has been described previously (

Garcia-Manero G et al., Am J Hematol 1999; 60(2): 130-5
,
Dingli D et al., Chest 2001, 120(3): 801-8
), but the mechanisms contributing to this potentially hazardous condition await further elucidation. Bone morphogenetic protein receptors (BMPR) modulate the size of the hematopoetic niche (
Zhang J et al., Nature 2003, 425(6960): 836-41
), with an inhibitory effect on myeloproliferation. In the pulmonary vascular bed, a decreased or deficient expression of BMPR has been shown to result in the proliferation of vascular smooth-muscle cells, asymmetric neointimal hyperplasia in small pulmonary arteries and subsequent pulmonary hypertension (
Lane KB et al., Nat Genet 2000, 26(1):81-4
;
Du L et al, N Engl J Med 2003, 348(6): 500-9
). We hypothesized that, in patients suffering from MPS and pulmonary hypertension, changes in the expression of BMPR and subsequent signalling molecules Angiopoietin-1 (Ang-1) and its receptor, TIE-2, may occur not only in the lung, but also in the bone marrow and correspond with enhanced myeloproliferation in vitro.

Bone marrow stromal cells were cultured from

  • patients with pulmonary hypertension and MPS (n=2),

  • patients with MPS and no evidence of pulmonary hypertension (n=3) and

  • healthy controls (n=3).

The cultured cells were subjected to Western Blot analysis for the expression of BMP receptors BMPR-1A and BMPR-2, Angiopoietin-1 and TIE-2. Furthermore, a modified long-term culture initiating cell (LTC-IC) assay was established using the cultured bone marrow stromal cells as layers for autologous and allogeneic progenitor cell assays.

The two patients suffering from both, MPS and pulmonary hypertension, showed a diminished expression of BMPR-1A and an enhanced expression of Ang-1 and TIE-2 in cultured stromal cells when compared to patients with MPS alone and to healthy controls. In one of the two patients, a three- to fourfold increase in the number of long-term culture-initiating cells after seeding of CD34-positive cells and of bone marrow mononuclear cells from healthy donors and from the other patients included was observed in modified LTC-IC assays.

Our observations argue in favour of changes in BMP receptor expression and signalling with impact not only on pulmonary hypertension as described before, but also on the emergence of a myeloproliferative state.

Topics:
bone morphogenetic proteins, hematopoietic stem cells, myeloproliferative disease, pulmonary hypertension, signal transduction, angiopoietins, cd34 antigens, molecule, western blotting, bone marrow

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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