During embryonic development, the growth of blood vessels requires the coordinated activation of endothelial receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptor-2 (VEGFR-2) and Tie-2. Similarly, in adulthood, activation of endothelial RTKs has been shown to enhance development of the collateral circulation and improve blood flow to ischemic tissues. Recent evidence suggests that RTK activation is negatively regulated by protein tyrosine phosphatases (PTPs). In this study, we used the nonselective PTP inhibitor bis(maltolato)oxovanadium IV (BMOV) to test the potential efficacy of PTP inhibition as a means to enhance endothelial RTK activation and improve collateral blood flow. In cultured endothelial cells, pretreatment with BMOV augmented VEGFR-2 and Tie-2 tyrosine phosphorylation and enhanced VEGF- and angiopoietin-1-mediated cell survival. In rat aortic ring explants, BMOV enhanced vessel sprouting, a process that can be influenced by both VEGFR-2 and Tie-2 activation. Moreover, 2 wk of BMOV treatment in a rat model of peripheral vascular disease enhanced collateral blood flow similarly to VEGF, and after 4 wk, BMOV was superior to VEGF. Taken together, these studies provide evidence that PTPs are important regulators of endothelial RTK activation and for the first time demonstrate the potential utility of phosphatase inhibition as a means to promote collateral development and enhance collateral blood flow to ischemic tissue.
Background The Renal Angina Index (RAI) is a validated screening tool used at 12 h of pediatric intensive care unit (PICU) admission to predict severe acute kidney injury (AKI) on day 3 of PICU stay. A measured or height-imputed baseline serum creatinine (SCr) is required for AKI diagnosis and RAI calculation, yet these are often lacking. We assessed an age-based, height-independent baseline SCr calculation and compared the RAI values employing this method to their historical counterpart. Methods An electronic algorithm was implemented to generate RAI score for patients admitted to our PICU. We reviewed 157 consecutive patient records from May 2017, until we cumulated 100 with a valid RAI calculation. We compared RAI scores using the age-based SCr imputation method of Pottel to the historical RAI. Our primary outcome was a difference in the rate of RAI fulfillment (≥8) reclassification between methods. Results Of the first 100 patients, 27 had measured baseline SCr and 73 used height imputation. Only two patients had RAI reclassified with the Pottel method (one in each direction). Being small for age or older were associated with ≥25% overestimation of the baseline SCr in 20 patients with the Pottel method compared with height imputation. 15/157 patients had a falsely positive RAI due to lack of measured baseline SCr and height. Conclusion The age-based method to estimate baseline SCr offers a viable height-independent alternative for RAI calculation. While less precise than a height-based approach, this lack of precision rarely leads to reclassification of patient RAI status.
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