{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:23:15Z","timestamp":1787836995941,"version":"build-2784847793"},"reference-count":60,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":24,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Microcirculation"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To propose and make testable a mechanistic hypothesis for post\u2010exertional malaise (PEM) in a clinically distinct subset of Long COVID patients, in whom delayed exertional symptoms coexist with consistently normal macrovascular investigations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Established vascular\u2010biology literature is synthesized into an integrated, falsifiable model centered on endothelial nitric oxide synthase (eNOS) uncoupling, from which mechanism\u2010specific predictions and a dynamic pre\u2010\/post\u2010exertion biomarker validation framework are derived.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We propose that SARS\u2010CoV\u20102\u2010induced endotheliitis activates inducible nitric oxide synthase and silently depletes the tetrahydrobiopterin (BH4) pool on return to activity, shear\u2010stress activation of structurally intact eNOS against a depleted BH4 background yields superoxide rather than nitric oxide, generating peroxynitrite that sustains a self\u2010amplifying nitro\u2010oxidative cycle. The Two\u2010Threshold Model distinguishes a PEM threshold from a shear\u2010stress\u2010tolerance threshold and predicts that prolonged immobility may paradoxically erode endothelial function. eNOS uncoupling is positioned as one node among alternative microvascular pathways, and autonomic findings are proposed to be secondary within this phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This phenotype\u2010specific, falsifiable hypothesis yields mechanism\u2010derived predictions and rehabilitation implications consistent with symptom\u2010contingent pacing guidance; it does not claim to explain all Long COVID presentations.<\/jats:p>\n                  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Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9027-4189","authenticated-orcid":false,"given":"Konstantinos Y.","family":"Karipidis","sequence":"additional","affiliation":[{"name":"Department of Physiotherapy, Faculty of Health Sciences International Hellenic University Alexander Campus  Thessaloniki 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