Citations

Background— Endothelial progenitor cells (EPCs) promote neovascularization and endothelial repair. Renal artery stenosis (RAS) may impair renal function by inducing intrarenal microvascular injury and remodeling. We investigated whether replenishment with EPCs would protect the renal microcirculation in chronic experimental renovascular disease. Methods and Results— Single-kidney hemodynamics and function were assessed with the use of multidetector computed tomography in vivo in pigs with RAS, pigs with RAS 4 weeks after intrarenal infusion of autologous EPCs, and controls. Renal microvascular remodeling and angiogenic pathways were investigated ex vivo with the use of micro–computed tomography, histology, and Western blotting. EPCs increased renal expression of angiogenic factors, stimulated proliferation and maturation of new vessels, and attenuated renal microvascular remodeling and fibrosis in RAS. Furthermore, EPCs normalized the blunted renal microvascular and filtration function. Conclusions— The present study shows that a single intrarenal infusion of autologous EPCs preserved microvascular architecture and function and decreased microvascular remodeling in experimental chronic RAS. It is likely that restoration of the angiogenic cascade by autologous EPCs involved not only generation of new vessels but also acceleration of their maturation and stabilization. This contributed to preserving the blood supply, hemodynamics, and function of the RAS kidney, supporting EPCs as a promising therapeutic intervention for preserving the kidney in renovascular disease.

In the Mayo Clinic Cohort Study of Oophorectomy and Aging, women who had both ovaries removed before reaching natural menopause experienced a long-term increased risk of parkinsonism, cognitive impairment or dementia, and depressive and anxiety symptoms. Here, we discuss five possible mechanistic interpretations of the observed associations; first, the associations may be non-causal because they result from the confounding effect of genetic variants or of other risk factors; second, the associations may be mediated by an abrupt reduction in levels of circulating estrogen; third, the associations may be mediated by an abrupt reduction in levels of circulating progesterone or testosterone; fourth, the associations may be mediated by an increased release of gonadotropins by the pituitary gland; and fifth, genetic variants may modify the hormonal effects of bilateral oophorectomy through simple or more complex interactions. Results from other studies are cited as evidence for or against each possible mechanism. These putative causal mechanisms are probably intertwined, and their clarification is a research priority.

Learning Objectives Analyze the clinical trial data for the treatment of breast cancer. Evaluate the risk of cardiotoxicity associated with the use of trastuzumab. Design and conduct a practical approach to managing patients with trastuzumab-associated cardiotoxicity. This article is available for continuing medical education credit at CME.TheOncologist.com.

Objective— Farnesoid X Receptor (FXR) mediates important signaling functions of bile acids in diverse cell types including those residing in the vascular wall. Indeed, recent work has identified FXR as a potential regulator of vascular structure and function in part through transcriptional activation of MMP-9. However, the signal transduction pathways linking bile acids to changes in actin cytoskeleton that are responsible for bile acid-induced vascular cell migration remain unexplored. Methods and Results— The FXR agonist and prototypical bile acid, chenodeoxycholic acid (CDCA), significantly increased endothelial cell (EC) motility, as analyzed by time lapse video microscopy, and tube formation, an in vitro correlate for angiogenesis. Increased cell motility was associated with prominent increases in focal adhesion (FA) plaques and was inhibited by FXR or MMP-9 siRNA, indicating a FXR-MMP-9-dependency of this signaling pathway. Mechanistically, incubation of cells with CDCA was associated with phosphorylation of a key FA protein, Focal Adhesion Kinase (FAK) at Y397 but not at Y576/577, or Y925. Studies using a site-specific phosphorylation mutant (phosphodeficient) of FAK revealed that FAK phosphorylation at tyrosine residue −397 was required for CDCA induced activation of the downstream FA assembly protein, paxillin. Lastly, siRNA-based silencing of FAK as well as phosphodeficient FAK mutant inhibited CDCA induced upregulation of MMP-9, cell motility, and vascular tube formation. Conclusion— Thus, this study demonstrates a pivotal role for FAK in the process of FXR-induced and MMP-9-dependent EC motility and vascular tube formation.