Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling.

Endothelial cell (EC) sensing of wall fluid shear stress (FSS) from blood flow governs vessel remodeling to maintain FSS at a specific magnitude or set point in healthy vessels. Low FSS triggers inward remodeling to restore normal FSS but the regulatory mechanisms are unknown. In this paper, we describe the signaling network that governs inward artery remodeling. FSS induces Smad2/3 phosphorylation through the type I transforming growth factor (TGF)-ß family receptor Alk5 and the transmembrane protein Neuropilin-1, which together increase sensitivity to circulating bone morphogenetic protein (BMP)-9. Smad2/3 nuclear translocation and target gene expression but not phosphorylation are maximal at low FSS and suppressed at physiological high shear. Reducing flow by carotid ligation in rodents increases Smad2/3 nuclear localization, while the resultant inward remodeling is blocked by the EC-specific deletion of Alk5. The flow-activated MEKK3/Klf2 pathway mediates the suppression of Smad2/3 nuclear translocation at high FSS, mainly through the cyclin-dependent kinase (CDK)-2-dependent phosphosphorylation of the Smad linker region. Thus, low FSS activates Smad2/3, while higher FSS blocks nuclear translocation to induce inward artery remodeling, specifically at low FSS. These results are likely relevant to inward remodeling in atherosclerotic vessels, in which Smad2/3 is activated through TGF-ß signaling.

Equity in medical education: Addressing microaggressions and discrimination on the wards.

PURPOSE: Existing frameworks to address instances of microaggressions and discrimination in the clinical environment have largely been developed for faculty and resident physicians, creating a lack of resources for medical students. METHODS: We implemented a workshop to prepare pre-clinical medical/dental students to recognize and respond to microaggressions. Participants in three cohorts from 2018 to 2020 completed pre- and post-workshop surveys assessing the prevalence of exposure to clinical microaggressions and the workshop's effect on mitigating commonly perceived barriers to addressing microaggressions. RESULTS: Of 461 first-year medical and dental students who participated, 321 (69.6%) provided survey responses. Over 80% of students reported experiencing microaggressions, with women and URM students over-represented. After the workshop, participants reported significant reductions in barriers to addressing microaggressions and discrimination, including recognizing incidents, uncertainty of what to say or do, lack of allies, lack of familiarity with institutional policies, and uncertainty of clinical relevance. The workshop was similarly effective in-person and virtual formats. CONCLUSIONS: Most medical/dental student respondents reported experiencing microaggressions in the clinical setting, particularly female and URM students. Our workshop mitigated most perceived challenges to responding to microaggressions. Future interventions across institutions should continue to equip students with the tools they need to address and respond to microaggressions.

Student-Led Efforts to Advance Anti-Racist Medical Education.

Over the past decade, medical schools across the United States have increasingly dedicated resources to advancing racial and social justice, such as by supporting diversity and inclusion efforts and by incorporating social medicine into the traditional medical curricula. While these changes are promising, the academic medicine community must apply an anti-racist lens to every aspect of medical education to equip trainees to recognize and address structural inequities. Notably, organizing and scholarly work led by medical students has been critical in advancing anti-racist curricula. In this article, the authors illustrate how student activism has reshaped medical education by highlighting examples of student-led efforts to advance anti-racist curricula at Harvard Medical School (HMS) and at the University of California, San Francisco (UCSF) School of Medicine. HMS students collaborated with faculty to address aspects of existing clinical practice that perpetuate racism, such as the racial correction factor in determining kidney function. They also responded to the existing curricula by noting missed opportunities to discuss structural racism, and they planned supplemental sessions to address these gaps. At UCSF, students identified specific avenues to improve the rigor of social medicine courses and developed new curricula to equip students with skills to confront and work to dismantle racism. The authors describe how HMS students, in an effort to improve the learning environment, developed a workshop to assist students in navigating microaggressions and discrimination in the clinical setting. At UCSF, students partnered with faculty and administration to advocate pass/fail grading for clerkships after university data revealed racial disparities in students' clerkship assessments. In reviewing these examples of students' advocacy to improve their own curricula and learning environments, the authors aim to provide support for students and faculty pursuing anti-racist curricular changes at their own institutions.

Building a Tool Kit for Medical and Dental Students: Addressing Microaggressions and Discrimination on the Wards.

Introduction: Microaggressions, subtle slights related to characteristics such as race, gender, or sexual orientation, in a clinical setting can sabotage the therapeutic alliance. Curricula tailored specifically towards medical students that raise awareness of microaggressions and aim to change behavior are absent. Methods: We created a 2-hour workshop to prepare preclinical medical and dental students to recognize and respond to microaggressions in clinical practice. The workshop consisted of a didactic portion describing microaggressions and strategies for responding to them and a case-based small-group portion to practice strategies. Participants completed electronic pre- and postworkshop surveys. Results: Of 163 students participating in the workshop, 121 (74%) completed the preworkshop survey, 105 (64%) completed the postworkshop survey, and 81 (50%) completed both. Preworkshop, 48% reported female gender, and 36% reported underrepresented in medicine status. The majority (77%) had witnessed or experienced microaggressions in the clinical setting, and 69% reported very good or excellent familiarity with the concept of microaggressions. The curriculum appeared to significantly mitigate challenges associated with microaggressions, including reductions in perceived difficulty in identifying microaggressions (p < .001), being unsure what to do or say (p < .001), improvements in familiarity with institutional support systems (p < .001), and awareness of the clinical relevance of microaggressions (p < .001). Discussion: Given the high self-reported prevalence of microaggressions in the clinical setting, students need the skills to respond. This innovative session improves readiness to address microaggressions by helping participants build and practice these skills in a supportive environment.

Endothelial-to-mesenchymal transition drives atherosclerosis progression.

The molecular mechanisms responsible for the development and progression of atherosclerotic lesions have not been fully established. Here, we investigated the role played by endothelial-to-mesenchymal transition (EndMT) and its key regulator FGF receptor 1 (FGFR1) in atherosclerosis. In cultured human endothelial cells, both inflammatory cytokines and oscillatory shear stress reduced endothelial FGFR1 expression and activated TGF-ß signaling. We further explored the link between disrupted FGF endothelial signaling and progression of atherosclerosis by introducing endothelial-specific deletion of FGF receptor substrate 2 α (Frs2a) in atherosclerotic (Apoe(-/-)) mice. When placed on a high-fat diet, these double-knockout mice developed atherosclerosis at a much earlier time point compared with that their Apoe(-/-) counterparts, eventually demonstrating an 84% increase in total plaque burden. Moreover, these animals exhibited extensive development of EndMT, deposition of fibronectin, and increased neointima formation. Additionally, we conducted a molecular and morphometric examination of left main coronary arteries from 43 patients with various levels of coronary disease to assess the clinical relevance of these findings. The extent of coronary atherosclerosis in this patient set strongly correlated with loss of endothelial FGFR1 expression, activation of endothelial TGF-ß signaling, and the extent of EndMT. These data demonstrate a link between loss of protective endothelial FGFR signaling, development of EndMT, and progression of atherosclerosis.