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Summary The Hairy-related transcription factor family of Notch- and ALK1-downstream transcriptional repressors, called Hrt/Hey/Hesr/Chf/Herp/Gridlock, has complementary and indispensable functions for vascular development. While mouse embryos null for either Hrt1/Hey1 or Hrt2/Hey2 did not show early vascular phenotypes, Hrt1/Hey1; Hrt2/Hey2 double null mice (H1ko/H2ko) showed embryonic lethality with severe impairment of vascular morphogenesis. It remained unclear, however, whether Hrt/Hey functions are required in endothelial cells or vascular smooth muscle cells. In this study, we demonstrate that mice with endothelial-specific deletion of Hrt2/Hey2 combined with global Hrt1/Hey1 deletion (H1ko/H2eko) show abnormal vascular morphogenesis and embryonic lethality. Their defects were characterized by the failure of vascular network formation in the yolk sac, abnormalities of embryonic vascular structures and impaired smooth muscle cell recruitment, and were virtually identical to the H1ko/H2ko phenotypes. Among signaling molecules implicated in vascular development, Robo4 expression was significantly increased and activation of Src family kinases was suppressed in endothelial cells of H1ko/H2eko embryos. The present study indicates an important role of Hrt1/Hey1 and Hrt2/Hey2 in endothelial cells during early vascular development, and further suggests involvement of Robo4 and Src family kinases in the mechanisms of embryonic vascular defects caused by the Hrt/Hey deficiency. genesis 52:897–906, 2014. © 2014 Wiley Periodicals, Inc.

The Hairy-related transcription factor family of Notch- and ALK1-downstream transcriptional repressors, called Hrt/Hey/Hesr/Chf/Herp/Gridlock, has complementary and indispensable functions for vascular development. While mouse embryos null for either Hrt1/Hey1 or Hrt2/Hey2 did not show early vascular phenotypes, Hrt1/Hey1; Hrt2/Hey2 double null mice (H1(ko) /H2(ko) ) showed embryonic lethality with severe impairment of vascular morphogenesis. It remained unclear, however, whether Hrt/Hey functions are required in endothelial cells or vascular smooth muscle cells. In this study, we demonstrate that mice with endothelial-specific deletion of Hrt2/Hey2 combined with global Hrt1/Hey1 deletion (H1(ko) /H2(eko) ) show abnormal vascular morphogenesis and embryonic lethality. Their defects were characterized by the failure of vascular network formation in the yolk sac, abnormalities of embryonic vascular structures and impaired smooth muscle cell recruitment, and were virtually identical to the H1(ko) /H2(ko) phenotypes. Among signaling molecules implicated in vascular development, Robo4 expression was significantly increased and activation of Src family kinases was suppressed in endothelial cells of H1(ko) /H2(eko) embryos. The present study indicates an important role of Hrt1/Hey1 and Hrt2/Hey2 in endothelial cells during early vascular development, and further suggests involvement of Robo4 and Src family kinases in the mechanisms of embryonic vascular defects caused by the Hrt/Hey deficiency.

SummaryWe report on a 25-year-old female heart transplant patient who presented with recurrent episodes of cellular rejection due to decreased adherence to immunosuppressive therapy. She received a heart transplantation in 1994 when she was 10 years old. In order to improve her adherence to immunosuppressive therapy, switching to the once-daily extended-release formulation of tacrolimus was performed in a step-wise fashion. First, the twice-daily formulation of cyclosporin A was replaced with the twice-daily preparation of tacrolimus. When the trough blood levels of tacrolimus reached a plateau in the range of 5.0ng/mL, it was changed to the once-daily extended-release formulation of tacrolimus after confirming the absence of new rejection episodes. There were no significant changes in renal function before and after the switch. After being discharged from the hospital, the patient made significant advancements in adherence to immunosuppressive therapy. Her subsequent clinical course was uneventful, with no adverse events observed. Most patients who undergo solid organ transplantation must receive lifelong immunosuppressive therapy. This case demonstrates that conversion to the extended-release formulation of tacrolimus from other calcineurin inhibitor preparations is a reasonable choice to consider in the management of compromised immunosuppressive therapy adherence in heart transplant patients during the late posttransplant period.