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This active transport of LDL can now adequately explain why plaques (atheromas) appear under an intact, uninjured endothelium. However, the LDL transcytosis hypothesis is still questionable, mainly because the process serves no clear physiological purpose. Moreover, central components of the putative LDL transcytosis apparatus are shared by the counter process of cholesterol efflux and reverse cholesterol transport (RCT) and therefore can essentially create an energy\u2010wasting futile cycle and paradoxically be pro\u2010 and antiatherogenic simultaneously. Hence, by critically reviewing the literature, we wish to put forward an alternative interpretation that, in our opinion, better fits the experimental evidence. We assert that most of the accumulating cholesterol (mainly as LDL) reaches the intima not from the lumen by transcytosis, but from the artery\u2019s inner layers: the adventitia and media. We have named this directional cholesterol transport transmural cholesterol flux (TCF). We suggest that excess cholesterol, diffusing from the avascular (i.e., devoid of blood and lymph vessels) media\u2019s smooth muscle cells, is cleared by the endothelium through its apical membrane. A plaque is formed when this cholesterol clearance rate lags behind its rate of arrival by TCF.<\/jats:p>","DOI":"10.1155\/2022\/2253478","type":"journal-article","created":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T04:20:25Z","timestamp":1649996425000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Atherogenesis, Transcytosis, and the Transmural Cholesterol Flux: A Critical Review"],"prefix":"10.1155","volume":"2022","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0948-1504","authenticated-orcid":false,"given":"Doron","family":"Goldberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6762-2408","authenticated-orcid":false,"given":"Soliman","family":"Khatib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,14]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.17305\/bjbms.2019.4320"},{"key":"e_1_2_9_2_2","first-page":"675","article-title":"Response to injury and atherogenesis","volume":"86","author":"Ross R.","year":"1977","journal-title":"The American Journal of Pathology"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.15.5.551"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2020.09.020"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2018.00130"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.21037\/biotarget.2019.08.03"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/607120"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.190587"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1140-4"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvv218"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13516"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.138.4.877"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.196170"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R083121"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi101657j"},{"key":"e_1_2_9_16_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.135392"},{"key":"e_1_2_9_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000101182.89118.E5"},{"key":"e_1_2_9_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.038571"},{"key":"e_1_2_9_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.06.003"},{"key":"e_1_2_9_20_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.091287"},{"key":"e_1_2_9_21_2","first-page":"1660","volume-title":"Williams Textbook of Endocrinology","author":"Semenkovich C. 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