Editorial: Endothelial-to-mesenchymal transition in cardiovascular disease

Endothelial-to-mesenchymal transition (EndMT) is a process through which endothelial cells (ECs) transition into mesenchymal cells and gain invasive and migratory properties. During this process, ECs can delaminate from their cell layer and invade the underlying tissue. In the classical form of EndMT, this is accompanied by downregulation of EC markers such as CD31 and VE-cadherin with concomitant upregulation of mesenchymal markers such as -SMA (alpha-smooth muscle actin) and PDGFR (platelet-derived growth factor receptor alpha), vimentin (VIM), and N-cadherin (CDH2) 1 . However, it is now known that EndMT can be partial 2 and in some cases transient 3 . EndMT is a fundamental process during early development 4 and has also been identified in a multitude of cardiovascular disease processes, including atherosclerosis [5][6][7][8] , valvular heart disease, peripheral artery disease 9 , and myocardial infarction 10 . Growing evidence for EndMT in human pathologies point to the clinical relevance of EndMT in cardiovascular diseases 5,11,12 .The collection of the research articles presented herein provides new insights into the molecular mechanisms and importance of EndMT in cardiovascular physiology and disease. The research highlights the complexities of the EndMT process, including distinctions among different EndMTinducing stimuli. The relevant actions of TGFβ1, TGFβ2, TNFα, and flow, among other mediators, are explored.Zhang et al. 13 present a novel mechanistic link between TGF2 and Wnt signaling pathway in human aortic endothelial cells and mouse atherosclerotic plaques. Exposure of cultured endothelial cells to TGF2 for 3 days upregulated -SMA and PDGFR and downregulated CD31 and VE-cadherin. After removal of TGF2 from the media, endothelial cell adhesion marker genes re-expressed, highlighting the plasticity of the response. Interestingly, deletion of Wnt2 significantly abolished the TGF2-driven EndMT. Wnt2 also colocalized with -SMA in aortic atherosclerosis in LDLR -/-mice fed Western diet for 12 weeks, but not in the chow diet-fed mice, indicating that Wnt2 expression is associated with atherosclerosis. A recent study by Chen et al. 14 reported that TGF induced populations of EndMT with proinflammatory features, and that Wnt signaling was altered upon EC-specific knock-out of TGF receptors 1 and 2 in atherogenic mice. The interplay among TGF2-mediated EndMT formation and Wnt2 in regulating the atherosclerosis burden is thus a key topic for further study.Another disease context for EndMT is calcified aortic valve disease (CAVD) 15 . Valvular endothelial cells can undergo EndMT and transdifferentiate into myofibroblast-like, with subsequent immune cell infiltration and calcification 16,17 . There is no medical treatment currently for CAVD and delineating molecular and cellular mechanisms of EndMT in this disease thus merits attention 18 . Nehl et al. 19 isolated ECs from porcine and human valvular tissue and exposed the cells with TGFβ1 or TNFα. Interestingly, the phenotype responses differed considerably between stimuli. After 7 days of TGFβ1 stimulation of human valvular ECs, the endothelial marker VWF (Von Willebrand factor) was downregulated, but PECAM-1 and VE-cadherin were upregulated. In contrast, stimulation with TNFα for 7 days resulted in consistent downregulation of EC markers, including VWF, PECAM-1, NOS3, and upregulation of the mesenchymal markers -SMA, VIM, CDH2, and VCAM-1. The porcine valvular ECs on the other hand did not substantially change their phenotype markers, nor was their migratory response like that of the human valvular ECs. This research highlights the diversity of EndMT profiles depending on the stimulus and potential for species-specific responses. Also in this issue, Chen et al. 20 review the emerging concept of EndMT as "an extreme spectrum of endothelial activation". The authors discuss TGFβ as a major inducer of EndMT. Disturbed flow is also sufficient to induce EndMT and under disturbed flow, FGF (Fibroblast growth factor) is downregulated, which exerts a positive effect on TGFR1. FGF and TGFβ have reciprocal actions in this regard. Furthermore, gene expression data analyses of ECs vs. cells having undergone EndMT vs. fibroblasts suggest that the set of EndMT genes differs from both ECs and fibroblasts.In another review, Huang and colleagues 21 provide a discussion of the mechanisms of EndMT in atherosclerosis and the different stimuli used by researchers to induce EndMT in culture, including TGFβ, interleukin-1 (IL-1β), oxidized low-density lipoprotein (oxLDL), Hydrogen peroxide (H2O2), and shear stress. The TGFβ signaling pathway, bone morphogenic protein (BMP) signaling pathway and NOTCH signaling pathway in EndMT induction are reviewed. Preventing EndMT to treat atherosclerosis is considered 21 . Finally, Jiang et al. 22 review the role of EndMT in vascular calcification, also with consideration to therapeutic strategies.Collectively, these research articles and reviews add to our understanding of EndMT in cardiovascular disease. The diversity of phenotypes and the differences among drivers of EndMT highlight the complexity of this remarkable re-wiring of endothelial cells. Ultimately, proving disease-altering roles for EndMT requires further attention, with the exciting possibility of disease-mitigating strategies.Andueza A et al. -TGFR1 and 2 EC-specific KO mice showed less atheroma compared to controls. This is associated with a decrease in inflammatory and ECM-EndMT, but not all EndMT clusters are abolished. Evrard et al. 5 HFD-induced Atherosclerosis.Cell culture.-Using Lineage tracing mice, ECs can progress and give rise to Fap+ cells (EndMT with fibroblast-like features). % of Fap+ cells increase in the cap with more chronic HFD feeding.-After 30 weeks, the majority of Fap+ cells did not express VE-cadherin (complete EndMT) (FSP-1/CD31, FSP-1/VWF).-TGFβ alone did not induce the same phenotype (EndMT with fibroblasts-like features) but it needs H2O2 or Hypoxia co-treatment to push the phenotype. Cell migration was used as a functional assay.Moonen et al. 23 Ex vivo.TAC-induced mouse model.Cell culture. -HUVECs and HAECs treated with TGFβ1 induces EndMT but the superimposed LSS prevents that.Mahmoud et al. 24 Ex vivo.HFD-Induced atherosclerosis.Zebrafish model.Mouse/ Zebrafish -TWIST1 and GATA4/ co-localized with CD31 are preferentially expressed in low shear areas in porcine aorta.-The Orbital shaker model used to assess TWIST1/CD31 and GATA4/CD31 positive cells in culture after 72h.-Twist1 KO in ECs reduces atherosclerosis.-Zebrafish embryos: twist1 enhanced under static compared to flow.-Proliferation was assessed as a functional assay for EndMT.Zhang et al.* 13 In vitro -Cell Culture.HFD-Induced atherosclerosis.Mouse -TGFβ2 promotes EndMT after 3 days in culture: downregulation of CD31/VE-cadherin, upregulation of α-SMA/PDGFRα.-The EndMT is reversed after removal of TGFβ2 by 2 days.-HFD compared to chow diet feeding after 12 weeks in LDLR -/-mice induces some of the phenotype.Tombor et al. 3 LAD-ligation model of MI.-scRNA seq of non-cardiomyocytes showed induction of mesenchymal cells with increase in FN1, Vimentin, Serpine1, MMP14.-Cdh5-lineage tracing confirmed induction of GFP+ ECs with mesenchymal markers: Col1a1, Col3A1, Serpine 1.-TGFβ2 treatment in HUVECs after 3 days induces calponin, SM22, and withdrawal of TGFβ2 reverse the process. -Porcine valvular ECs did not show the same response.-Migration (scratch wound) and calcification were used for functional assay.Zhong et al. 27 Cell Culture: cells treated with TGFβ1, TNF-α, or H2O2.

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