Clonal endothelial progenitor cells (EPCs) have been implicated in the aberrant vascular growth that features infantile hemangioma (IH), the most common benign vascular tumor in childhood that may cause ulceration, bleeding, and/or permanent disfigurement. Endothelial colony-forming cells (ECFCs), truly endothelial EPCs endowed with clonal ability and capable of forming patent vessels in vivo, remodel their Ca(2+) toolkit in tumor-derived patients to acquire an adaptive advantage. Particularly, they upregulate the proangiogenic store-operated Ca(2+) entry (SOCE) pathway due to the overexpression of its underlying components, that is, stromal interaction molecule 1 (Stim1), Orai1, and transient receptor potential canonical 1 (TRPC1). The present work was undertaken to assess whether and how the Ca(2+) signalosome is altered in IH-ECFCs by employing Ca(2+) and nitric oxide (NO) imaging, real-time polymerase chain reaction, western blotting, and functional assays. IH-ECFCs display a lower intracellular Ca(2+) release in response to either pharmacological (i.e., cyclopiazonic acid) or physiological (i.e., ATP and vascular endothelial growth factor) stimulation. Conversely, Stim1, Orai1, and TRPC1 transcripts and proteins are normally expressed in these cells and mediate a constitutive SOCE, which is sensitive to BTP-2, La(3+), and Pyr6 and recharges the intracellular Ca(2+) pool. The resting SOCE in IH-ECFCs is also associated to an increase in their proliferation rate and the basal production of NO compared to normal cells. Likewise, the pharmacological blockade of SOCE and NO synthesis block IH-ECFC growth. Collectively, these data indicate that the constitutive SOCE activation enhances IH-ECFC proliferation by augmenting basal NO production and sheds novel light on the molecular mechanisms of IH.

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The pediatric ultrasound measurement of the inferior vena cava (IVC) and aorta (AO) with the study of the collapsibility index (CI) and of IVC-to-AO ratio (IVC/AO) can provide clinicians in the acute care setting with information on abnormal volume status but one of the major limitations is a lack of reference normal values by body surface area (BSA) and age. The aim of this study was to provide reference ranges for the sonographic measurement of IVC, AO, and IVC/AO ratio in healthy Caucasian Italian children. Methods: We enrolled prospectively 516 healthy Caucasian Italian children aged between 1 month and 16 years. Echocardiographic IVC and AO diameters were collected and presented separately for children aged 1 year and for children aged over 1 year. For children >1 year we categorized subjects into 3 years classes. CI and IVC/AO for the systolic aortic diameter were then calculated. For children over 1 year, age reference ranges were age-related or BSA-related; for children of 1 year, reference ranges were determined with their 90% confidence intervals regardless of age and of BSA. Results: Tables and charts with reference ranges for all the echocardiographic measurements are presented for children aged >1 year according to age and BSA. The equations to obtain percentile and Z-score for each echocardiographic measurement are provided. The reference ranges for children aged 1 year are shown considering the small 90% confidence intervals for upper and lower limits. CI was 30% (SD 17%) in children >1 year and 36% (SD 16%) in children <1 year. IVC/AOs showed agedependent values from 0.83 (SD 0.20) age <1 year to 1.22 (SD 0.31) in older subjects. Conclusions: We report reliable reference ranges for echocardiographic measurement of IVC, AO, CI, and IVC/AO for a Caucasian Italian healthy pediatric population.