Abstract

Neoangiogenesis, manifested as, for example high microvascular density (MVD), is an important feature of most solid tumors and also in the bone marrow of hematological malignancies. Very high MVD has been demonstrated in chronic myeloid leukemia and myelofibrosis (MF). In addition, MF marrows, as well as solid tumor vessels, display highly tortuous and branched vessels with caliber changes. However, the pathogenic mechanisms are poorly understood. Since pericyte (PC) deficiency has been described on similarly abnormal solid tumor vessels we studied vessel morphology and PC coverage in bone marrows from nine MF patients and nine controls as well as in three mouse models of MF. - In human MF marrows mean MVD was 6.2-fold higher compared to controls (P<0.001) and MF vessels displayed larger mean perimeters (89±61 μm vs. 19±9 μm; P<0.001). The cellular expression of VEGF-A was 6.6-fold higher in MF marrows than in controls (P<0.001). Unexpectedly, we found that 99±3 % of all MF vessels were PC-coated (i.e. postive for α-smooth muscle actin) compared with only 51±20 % in controls (P<0.001). To study whether these findings could be attributed to the abnormal megakaryocytopoiesis, typical for MF, we used mouse models of MF with genetic alterations affecting megakaryocyte differentiation:

  1. low expression of the transcription factor GATA-1 (GATA-1low),

  2. over-expression of thrombopoietin, or

  3. TPO over-expressing mice lacking expression of TGF-β1 (however, fibrosis does not develop in model 3).

In all 3 models wide and morphologically aberrant vessels were detected and microvascular density was significantly higher in marrows as well as in spleens (P<0.001 compared with wild type animals). All models displayed PC-coated bone marrow vessels, similar to the findings in human MF. Thus, processes leading to fibrosis, including TGF-β1, are not sufficient to deregulate angiogenesis - We conclude that human and mice MF marrow vessels display similar pathologic blood vessel architecture, with intense PC coverage, and genetic modifications of two molecules, viz GATA-1 and TPO, important for the regulation of megakaryocytopoiesis, might be of significance for this process.

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