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 Ca²⁺ signaling plays a crucial role in driving ECFC proliferation, migration, homing and neovessel formation. For instance, vascular endothelial growth factor (VEGF) triggers intracellular Ca²⁺ oscillations and stimulates angiogenesis in healthy ECFCs, whereas stromal derived factor-1α promotes ECFC migration through a biphasic Ca²⁺ signal. The Ca²⁺ 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 Ca²⁺ release from the endoplasmic reticulum is downregulated in tumor-derived ECFCs, while agonists-induced store-operated Ca²⁺ entry is up-regulated in renal cellular carcinoma and is unaltered in breast cancer and reduced in infantile hemangioma. This remodeling of the Ca²⁺ toolkit prevents VEGF-induced pro-angiogenic Ca²⁺ oscillations in tumor-derived ECFCs. An emerging theme of research is the dysregulation of the Ca²⁺ 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 Ca²⁺ signaling toolkit in ECFCs derived from umbilical cord blood and from peripheral blood of healthy donors, cancer patients and subjects affected by primary myelofibrosis.