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VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients



Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is characterized by persistent clinical symptoms following COVID-19.


To correlate biomarkers of endothelial dysfunction with persistent clinical symptoms and pulmonary function defects at distance from COVID-19.


Consecutive patients with long COVID-19 suspicion were enrolled. A panel of endothelial biomarkers was measured in each patient during clinical evaluation and pulmonary function test (PFT).


The study included 137 PASC patients, mostly male (68%), with a median age of 55 years. A total of 194 PFTs were performed between months 3 and 24 after an episode of SARS-CoV-2 infection. We compared biomarkers evaluated in PASC patients with 20 healthy volunteers (HVs) and acute hospitalized COVID-19 patients (n = 88). The study found that angiogenesis-related biomarkers and von Willebrand factor (VWF) levels were increased in PASC patients compared to HVs without increased inflammatory or platelet activation markers. Moreover, VEGF-A and VWF were associated with persistent lung CT scan lesions and impaired diffusing capacity of the lungs for carbon monoxide (DLCO) measurement. By employing a Cox proportional hazards model adjusted for age, sex, and body mass index, we further confirmed the accuracy of VEGF-A and VWF. Following adjustment, VEGF-A emerged as the most significant predictive factor associated with persistent lung CT scan lesions and impaired DLCO measurement.


VEGF-A is a relevant predictive factor for DLCO impairment and radiological sequelae in PASC. Beyond being a biomarker, we hypothesize that the persistence of angiogenic disorders may contribute to long COVID symptoms.

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Assistance Publique - Hôpitaux de Paris


Acute respiratory distress syndrome


American Thoracic Society


Area under the curve


Body mass index


C-reactive protein


Computer Tomography


Diffusing capacity of the lung for carbon monoxide


Fibroblast growth factor 2


Functional residual capacity


Global Lung Function Initiative


Ground glass opacities


High-resolution computed tomography


High-sensitivity cardiac troponin I


Idiopathic pulmonary fibrosis


Interquartile range


6-minute walk distance


Pulmonary arterial hypertension


Post-acute sequelae of COVID-19


Pulmonary hypertension


Placental growth factor


Pulmonary function test


Platelet-poor plasma


Receiver operator characteristics


Severe acute respiratory syndrome coronavirus-2


Standard deviation


Soluble P-selectin


Vascular cell adhesion protein 1


Vascular endothelial growth factor A


von Willebrand factor


Total lung capacity


  1. Centers for disease control and prevention (CDC). Post-COVID Conditions: Information for Healthcare Providers. :

  2. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV (2022) WHO clinical case definition working group on post-COVID-19 condition. a clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis 22(4):e102-7

    Article  CAS  PubMed  Google Scholar 

  3. Montani D, Savale L, Noel N, Meyrignac O, Colle R, Gasnier M et al (2022) Post-acute COVID-19 syndrome. Eur Respir Rev Off J Eur Respir Soc 31(163):210185

    Article  Google Scholar 

  4. Carfì A, Bernabei R, Landi F (2020) Gemelli against COVID-19 Post-acute care study group. persistent symptoms in patients after acute COVID-19. JAMA 324(6):603–5

    Article  PubMed  PubMed Central  Google Scholar 

  5. Xiong Q, Xu M, Li J, Liu Y, Zhang J, Xu Y et al (2021) Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 27(1):89–95

    CAS  Google Scholar 

  6. Ballering AV, van Zon SKR, Olde Hartman TC, Rosmalen JGM (2022) Lifelines corona research initiative persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study. Lancet Lond Engl 400(10350):452–61

    Article  CAS  Google Scholar 

  7. Huang L, Yao Q, Gu X, Wang Q, Ren L, Wang Y et al (2021) 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet Lond Engl 398(10302):747–758

    Article  CAS  Google Scholar 

  8. Huang L, Li X, Gu X, Zhang H, Ren L, Guo L et al (2022) Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study. Lancet Respir Med 10(9):863–876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Global Burden of Disease Long COVID Collaborators, Wulf Hanson S, Abbafati C, Aerts JG, Al-Aly Z, Ashbaugh C et al (2022) Estimated global proportions of individuals with persistent fatigue, cognitive, and respiratory symptom clusters following symptomatic COVID-19 in 2020 and 2021. JAMA 328(16):1604–1615

    Article  PubMed Central  Google Scholar 

  10. Mateu L, Tebe C, Loste C, Santos JR, Lladós G, López C, et al. Determinants of the Onset and Prognosis of the Post-COVID-19 Condition: A 2-Year Prospective Cohort Study [Internet]. SSRN; 2023. Retrieved July 13, 2023, from

  11. Yang C, Zhao H, Espín E, Tebbutt SJ (2023) Association of SARS-CoV-2 infection and persistence with long COVID. Lancet Respir Med.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Swank Z, Senussi Y, Manickas-Hill Z, Yu XG, Li JZ, Alter G et al (2023) Persistent Circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clin Infect Dis Off Publ Infect Dis Soc Am 76(3):e487–e490

    Article  Google Scholar 

  13. Patel MA, Knauer MJ, Nicholson M, Daley M, Van Nynatten LR, Cepinskas G et al (2023) Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning. Mol Med 29(1):26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gyöngyösi M, Alcaide P, Asselbergs FW, Brundel BJJM, Camici GG, da Costa Martins P et al (2023) Long COVID and the cardiovascular system-elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: a joint Scientific Statement of the ESC Working Groups on cellular biology of the heart and myocardial and pericardial diseases. Cardiovasc Res 119(2):336–56

    Article  PubMed  Google Scholar 

  15. Chioh FW, Fong SW, Young BE, Wu KX, Siau A, Krishnan S et al (2021) Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation. eLife 10:e64909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F et al (2020) Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 383(2):120–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Smadja DM, Mentzer SJ, Fontenay M, Laffan MA, Ackermann M, Helms J et al (2021) COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects. Angiogenesis 24(4):755–788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Philippe A, Chocron R, Gendron N, Bory O, Beauvais A, Peron N et al (2021) Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality. Angiogenesis 24(3):505–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Werlein C, Ackermann M, Stark H, Shah HR, Tzankov A, Haslbauer JD et al (2022) Inflammation and vascular remodeling in COVID-19 hearts. Angiogenesis 12:1–16

    Google Scholar 

  20. Smadja DM, Philippe A, Bory O, Gendron N, Beauvais A, Gruest M et al (2021) Placental growth factor level in plasma predicts COVID-19 severity and in-hospital mortality. J Thromb Haemost JTH 19(7):1823–1830

    Article  CAS  PubMed  Google Scholar 

  21. Faconti L, Farukh B, McNally RJ, Brett S, Chowienczyk PJ (2023) Impaired β2-adrenergic endothelium-dependent vasodilation in patients previously hospitalized with coronavirus disease 2019. J Hypertens.

    Article  PubMed  Google Scholar 

  22. Fogarty H, Townsend L, Morrin H, Ahmad A, Comerford C, Karampini E et al (2021) Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J Thromb Haemost JTH 19(10):2546–2553

    Article  CAS  PubMed  Google Scholar 

  23. Fogarty H, Ward SE, Townsend L, Karampini E, Elliott S, Conlon N et al (2022) Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction. J Thromb Haemost 20(10):2429–2438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH et al (2012) Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 40(6):1324–1343

    Article  PubMed  PubMed Central  Google Scholar 

  25. Stanojevic S, Graham BL, Cooper BG, Thompson BR, Carter KW, Francis RW et al (2017) Official ERS technical standards: global lung function initiative reference values for the carbon monoxide transfer factor for Caucasians. Eur Respir J 50(3):1700010

    Article  PubMed  Google Scholar 

  26. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1; 166(1):111–7

  27. Enright PL, Sherrill DL (1998) Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med 158(5 Pt 1):1384–1387

    Article  CAS  PubMed  Google Scholar 

  28. Bernheim A, Mei X, Huang M, Yang Y, Fayad ZA, Zhang N et al (2020) Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection. Radiology 295(3):200463

    Article  PubMed  Google Scholar 

  29. Wang Y, Dong C, Hu Y, Li C, Ren Q, Zhang X et al (2020) Temporal changes of CT findings in 90 patients with COVID-19 pneumonia: a longitudinal study. Radiology 296(2):E55-64

    Article  PubMed  Google Scholar 

  30. Guerin CL, Guyonnet L, Goudot G, Revets D, Konstantinou M, Chipont A et al (2021) Multidimensional proteomic approach of endothelial progenitors demonstrate expression of KDR restricted to CD19 Cells. Stem Cell Rev Rep 17(2):639–651

    Article  CAS  PubMed  Google Scholar 

  31. Dudley AC, Griffioen AW (2023) Pathological angiogenesis: mechanisms and therapeutic strategies. Angiogenesis 15:1–35

    Google Scholar 

  32. Ackermann M, Kamp JC, Werlein C, Walsh CL, Stark H, Prade V et al (2022) The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling. EBioMedicine 4(85):104296

    Article  Google Scholar 

  33. Kamp JC, Werlein C, Plucinski EKJ, Neubert L, Welte T, Lee PD et al (2023) Novel insight into pulmonary fibrosis and long COVID. Am J Respir Crit Care Med 207(8):1105–1107

    Article  PubMed  PubMed Central  Google Scholar 

  34. Barratt S, Medford AR, Millar AB (2014) Vascular endothelial growth factor in acute lung injury and acute respiratory distress syndrome. Respir Int Rev Thorac Dis 87(4):329–342

    CAS  Google Scholar 

  35. Miao H, Qiu F, Zhu L, Jiang B, Yuan Y, Huang B et al (2021) Novel angiogenesis strategy to ameliorate pulmonary hypertension. J Thorac Cardiovasc Surg 161(6):e417–e434

    Article  PubMed  Google Scholar 

  36. Eddahibi S, Humbert M, Sediame S, Chouaid C, Partovian C, Maître B et al (2000) Imbalance between platelet vascular endothelial growth factor and platelet-derived growth factor in pulmonary hypertension. effect of prostacyclin therapy. Am J Respir Crit Care Med 162:1493–9

    Article  CAS  PubMed  Google Scholar 

  37. Christou H, Yoshida A, Arthur V, Morita T, Kourembanas S (1998) Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol 18(6):768–776

    Article  CAS  PubMed  Google Scholar 

  38. Smadja DM, Gaussem P, Mauge L, Israël-Biet D, Dignat-George F, Peyrard S et al (2009) Circulating endothelial cells: a new candidate biomarker of irreversible pulmonary hypertension secondary to congenital heart disease. Circulation 119(3):374–381

    Article  PubMed  Google Scholar 

  39. Godinas L, Guignabert C, Seferian A, Perros F, Bergot E, Sibille Y et al (2013) Tyrosine kinase inhibitors in pulmonary arterial hypertension: a double-edge sword? Semin Respir Crit Care Med 34(5):714–724

    Article  PubMed  Google Scholar 

  40. Papaioannou AI, Kostikas K, Kollia P, Gourgoulianis KI (2006) Clinical implications for vascular endothelial growth factor in the lung: friend or foe? Respir Res 7(1):128

    Article  PubMed  PubMed Central  Google Scholar 

  41. Smadja DM, Nunes H, Juvin K, Bertil S, Valeyre D, Gaussem P et al (2014) Increase in both angiogenic and angiostatic mediators in patients with idiopathic pulmonary fibrosis. Pathol Biol (Paris) 62(6):391–394

    Article  CAS  PubMed  Google Scholar 

  42. Fukihara J, Kondoh Y (2016) Nintedanib (OFEV) in the treatment of idiopathic pulmonary fibrosis. Expert Rev Respir Med 10(12):1247–1254

    Article  CAS  PubMed  Google Scholar 

  43. Alfadda AA, Rafiullah M, Alkhowaiter M, Alotaibi N, Alzahrani M, Binkhamis K et al (2022) Clinical and biochemical characteristics of people experiencing post-coronavirus disease 2019-related symptoms: a prospective follow-up investigation. Front Med 9:1067082

    Article  Google Scholar 

  44. Patel MA, Knauer MJ, Nicholson M, Daley M, Van Nynatten LR, Martin C et al (2022) Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism. Mol Med 28(1):122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Patterson BK, Guevara-Coto J, Yogendra R, Francisco EB, Long E, Pise A et al (2021) Immune-based prediction of COVID-19 severity and Chronicity decoded using machine learning. Front Immunol 28(12):700782

    Article  Google Scholar 

  46. Patterson BK, Yogendra R, Guevara-Coto J, Mora-Rodriguez RA, Osgood E, Bream J et al (2023) Case series: maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequelae of COVID (PASC). Front Med 10:1122529

    Article  Google Scholar 

  47. Gupta A, Konnova A, Smet M, Berkell M, Savoldi A, Morra M et al (2023) Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments. J Clin Invest 133(6):e166032

    Article  PubMed  PubMed Central  Google Scholar 

  48. Vojdani A, Vojdani E, Saidara E, Maes M (2023) Persistent SARS-CoV-2 infection, EBV, HHV-6 and other factors may contribute to inflammation and autoimmunity in long COVID. Viruses 15(2):400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Osiaevi I, Schulze A, Evers G, Harmening K, Vink H, Kümpers P et al (2023) Persistent capillary rarefication in long COVID syndrome. Angiogenesis 26(1):53–61

    Article  CAS  PubMed  Google Scholar 

  50. Ebina M, Shimizukawa M, Shibata N, Kimura Y, Suzuki T, Endo M et al (2004) Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 169(11):1203–1208

    Article  PubMed  Google Scholar 

  51. Charfeddine S, Ibn Hadj Amor H, Jdidi J, Torjmen S, Kraiem S, Hammami R et al (2021) Long COVID 19 syndrome: is it related to microcirculation and endothelial dysfunction? insights from TUN-EndCOV study. Front Cardiovasc Med 8:745758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Charfeddine S, Ibnhadjamor H, Jdidi J, Torjmen S, Kraiem S, Bahloul A et al (2022) Sulodexide significantly improves endothelial dysfunction and alleviates chest pain and palpitations in patients with long-COVID-19: insights from TUN-EndCOV study. Front Cardiovasc Med 9:866113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Willems LH, Nagy M, Ten Cate H, Spronk HMH, Groh LA, Leentjens J et al (2022) Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19. Thromb Res 209:106–114

    Article  CAS  PubMed  Google Scholar 

  54. Willems LH, Jacobs LMC, Groh LA, Ten Cate H, Spronk HMH, Wilson-Storey B et al (2023) Vascular function, systemic inflammation, and coagulation activation 18 months after COVID-19 infection: an observational cohort study. J Clin Med 12(4):1413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Fan BE, Wong SW, Sum CLL, Lim GH, Leung BP, Tan CW et al (2022) Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: assessing the long-term outcomes in COVID-19 patients. Am J Hematol 97(7):915–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Philippe A, Gendron N, Bory O, Beauvais A, Mirault T, Planquette B et al (2021) Von Willebrand factor collagen-binding capacity predicts in-hospital mortality in COVID-19 patients: insight from VWF/ADAMTS13 ratio imbalance. Angiogenesis 24(3):407–411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Constantinescu-Bercu A, Kessler A, de Groot R, Dragunaite B, Heightman M, Hillman T et al (2023) Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome. J Thromb Haemost 21(1):94–100

    Article  PubMed  Google Scholar 

  58. Prasannan N, Heightman M, Hillman T, Wall E, Bell R, Kessler A et al (2022) Impaired exercise capacity in post-COVID-19 syndrome: the role of VWF-ADAMTS13 axis. Blood Adv 6(13):4041–4048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lorenzi O, Frieden M, Villemin P, Fournier M, Foti M, Vischer UM (2008) Protein kinase C-delta mediates von Willebrand factor secretion from endothelial cells in response to vascular endothelial growth factor (VEGF) but not histamine. J Thromb Haemost 6(11):1962–1969

    Article  CAS  PubMed  Google Scholar 

  60. Yang X, Jian Sun H, Rong Li Z, Zhang H, Jun Yang W, Ni B et al (2015) Gastric cancer-associated enhancement of von Willebrand factor is regulated by vascular endothelial growth factor and related to disease severity. BMC Cancer 15:80

    Article  PubMed  PubMed Central  Google Scholar 

  61. Matsushita K, Yamakuchi M, Morrell CN, Ozaki M, O’Rourke B, Irani K et al (2005) Vascular endothelial growth factor regulation of Weibel-Palade-body exocytosis. Blood 105(1):207–214

    Article  CAS  PubMed  Google Scholar 

  62. Geindreau M, Ghiringhelli F, Bruchard M (2021) Vascular endothelial growth factor, a key modulator of the anti-tumor immune response. Int J Mol Sci 22(9):4871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pang J, Xu F, Aondio G, Li Y, Fumagalli A, Lu M et al (2021) Efficacy and tolerability of bevacizumab in patients with severe Covid-19. Nat Commun 12(1):814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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This work was funded with grants from French national agency for research ANR SARCODO (Fondation de France). Aurélien Philippe was funded with grants from Mécénat Crédit Agricole Ile de France programme jeune talent.

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DMS, SG, and JLD designed the study. AP and DMS analyzed the data and wrote the manuscript. AP and PC performed statistical analysis. All authors reviewed and approved the final manuscript for publication.

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Correspondence to David M. Smadja.

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Philippe, A., Günther, S., Rancic, J. et al. VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients. Angiogenesis (2023).

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