Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play an important role in vascular health and disease as well as in regulating Estrogen actions in many cell types. We hypothesize that E2 may mediate its vascular protective actions via the regulation of miRNAs. Following initial screening, we found that E2 downregulates the levels of miR-193a-3p in ECs. Moreover, miR-193a-3p downregulation by miR-193a-3p-antimir mimicked the effects as E2 on EC growth, migration, and capillary formation. Restoring miR-193a-3p levels with mimics after E2 treatment abrogated the vasculogenic actions of E2, suggesting a key role of miR-193a-3p in E2-mediated EC-growth-promoting effects. We further investigated the cellular mechanisms involved and found that miR-193a-3p inhibits angiogenesis by blocking phosphoinositide-3-kinase (PI3K)/Akt-vascular endothelial growth factor (VEGF) and Activin receptor-like kinase 1 (ALK1)/SMAD1/5/8 signaling in ECs, both pathways that are important in E2-mediated vascular protection. Additionally, using reverse transcription polymerase chain reaction (RT-PCR), we demonstrate that E2 downregulates miR-193a-3p in ECs via Estrogen Receptor (ER)α, but not ERβ or G protein-coupled estrogen receptor (GPER). Moreover, these actions occur post-transcriptionally, as the expression of pri-miR-193a-3p was not affected. The anti-angiogenic actions of miR-193a-3p were also observed in in vivo Matrigel implant-based capillary formation studies in ovariectomized mice where E2 induced capillary formation, and these effects were abrogated in the presence of miR-193a-3p, but not in the control mimic. Assessment of miR-193a-3p levels in plasma collected from in vitro fertilization (IVF) subjects with low and high E2 levels showed significantly lower miR-193a-3p levels in responders during the high E2 period. Hence, our findings provide the first evidence that miR-193a-3p mimic inhibits angiogenesis whereas its antimir is angiogenic. Importantly, E2 mediates its regenerative actions on ECs/capillary formation by downregulating endogenous miR-193a-3p expression. Both miR-193a-3p mimic or antimir may represent important therapeutic molecules to prevent or to induce endothelial function in treating pathophysiologies associated with capillary growth.

Every day in the ICU, legal issues arise while treating sedated, unconscious, and legally incapacitated patients. Whenever a life-saving treatment cannot be discussed in a timely manner with an unconscious patient, doctors are required by law to act according to the substituted judgment standard. However, if it is not survival that is at stake, but conservation of reproduction and the potential side effects are significant, the decision-making process becomes much more difficult. Legal issues associated with possible harm to the patient on the one hand and ethical issues with presumable benefit of the intervention on the other hand give rise to difficult decisions. We present the case of a 24-year-old patient with Goodpasture syndrome. Because of rapid aggravation of kidney function and alveolar hemorrhage—the latter requiring an urgent initiation of mechanical ventilation—therapy with steroids, plasmapheresis, and cyclophosphamide was immediately required. Knowledge of the negative impact on fertility brought up the question about sperm cryopreservation. According to the substituted judgment standard, together with the mother of the patient and based on interdisciplinary evaluation of the situation with specialists from the reproductive endocrinology and urology department, the decision for a testicular sperm extraction in the absence of the possibility to obtain the patient’s informed consent was made. Immediate chemotherapy was initiated and continued after the procedure. The patient recovered from the acute illness and was informed retrospectively about the testicular sperm extraction, which he received extremely positively. Our aim is to highlight the legal objectives and ethical aspects of a non-lifesaving but fertility-preserving intervention in an unconscious patient. The need for decision-making in this kind of situation is rare and therefore challenging. The present case may serve to encourage and guide other doctors in similar situations.

Zusammenfassung: Ungewollte Kinderlosigkeit ist ein ernst zu nehmendes Problem. Für viele Paare stellt der Wunsch nach einem Kind einen zentralen Lebensinhalt dar. Gemäss der „World Health Organisation“ (WHO) liegt eine Sterilität vor, wenn trotz regelmässigem und ungeschütztem Geschlechtsverkehr nach 1 Jahr noch keine Schwangerschaft eingetreten ist. Die Prävalenz variiert je nach Land. Es wird geschätzt, dass in der westlichen Welt ca. jedes 7. Paar betroffen ist. Zahlreiche Gründe können für eine ungewollte Kinderlosigkeit verantwortlich sein. Vor Beginn einer Sterilitätstherapie sollten diese abgeklärt werden, um eine optimale Wahl der Sterilitätstherapie treffen zu können. Die assistiert-reproduktionsmedizinischen Techniken stellen wichtige Therapieoptionen mit guten Erfolgschancen dar. Mit dem Inkrafttreten des revidierten Fortpflanzungsmedizingesetztes der Schweiz ist es nun auch möglich, Verfahren, die früher nur im Ausland erfolgen konnten, im Inland durchzuführen. So kann mittlerweile Paaren mit schweren Erbleiden auch im eigenen Land eine Präimplantationsdiagnostik erfolgreich angeboten werden.