Calcium Signaling in Endothelial Colony Forming Cells in Health and Disease.

Endothelial colony forming cells (ECFCs) represent the only known truly endothelial precursors. ECFCs are released in peripheral circulation to restore the vascular networks dismantled by an ischemic insult or to sustain the early phases of the angiogenic switch in solid tumors. A growing number of studies demonstrated that intracellular Ca signaling plays a crucial role in driving ECFC proliferation, migration, homing and neovessel formation. For instance, vascular endothelial growth factor (VEGF) triggers intracellular Ca oscillations and stimulates angiogenesis in healthy ECFCs, whereas stromal derived factor-1α promotes ECFC migration through a biphasic Ca signal. The Ca toolkit endowed to circulating ECFCs is extremely plastic and shows striking differences depending on the physiological background of the donor. For instance, inositol-1,4,5-trisphosphate-induced Ca release from the endoplasmic reticulum is downregulated in tumor-derived ECFCs, while agonists-induced store-operated Ca entry is up-regulated in renal cellular carcinoma and is unaltered in breast cancer and reduced in infantile hemangioma. This remodeling of the Ca toolkit prevents VEGF-induced pro-angiogenic Ca oscillations in tumor-derived ECFCs. An emerging theme of research is the dysregulation of the Ca toolkit in primary myelofibrosis-derived ECFCs, as this myeloproliferative disorder may depend on a driver mutation in the calreticulin gene. In this chapter, I provide a comprehensive, but succinct, description on the architecture and role of the intracellular Ca signaling toolkit in ECFCs derived from umbilical cord blood and from peripheral blood of healthy donors, cancer patients and subjects affected by primary myelofibrosis.