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Linking ACE2 and angiotensin II to pulmonary immunovascular dysregulation in SARS-CoV-2 infection

Open AccessPublished:September 17, 2020DOI:https://doi.org/10.1016/j.ijid.2020.09.041

      Highlights

      • Dysregulation of angiotensin-converting enzyme 2 (ACE2) and angiotensin II may contribute to pulmonary vasoplegia in coronaviral disease.
      • ACE2 down-regulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected macrophages can increase cytokine production.
      • ACE2 down-regulation in SARS-CoV-2 in vessels can increase their responsiveness to inflammatory cytokines.
      • The observed increase in circulating angiotensin II in SARS-CoV-2 infection may increase cytokine production in endothelium and macrophages.

      Abstract

      Angiotensin-converting enzyme 2 (ACE2) is the receptor of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. ACE2 has been shown to be down-regulated during coronaviral infection, with implications for circulatory homeostasis. In COVID-19, pulmonary vascular dysregulation has been observed resulting in ventilation perfusion mismatches in lung tissue, causing profound hypoxemia. Despite the loss of ACE2 and raised circulating vasoconstrictor angiotensin II (AngII), COVID-19 patients experience a vasodilative vasculopathy. This article discusses the interplay between the immune system and pulmonary vasculature and how SARS-CoV-2-mediated ACE2 disruption and AngII may contribute to the novel vascular pathophysiology of COVID-19.

      Keywords

      Introduction

      Angiotensin-converting enzyme 2 (ACE2) is the receptor of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19) pandemic (
      • Hoffmann M.
      • Kleine-Weber H.
      • Schroeder S.
      • Kruger N.
      • Herrler T.
      • Erichsen S.
      • et al.
      SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.
      ). ACE2 is a carboxypeptidase that cleaves angiotensin II (AngII) into angiotensin-(1–7), countering the vasoconstrictive effect of the angiotensin converting enzyme 1 (ACE)–AngII– angiotensin II receptor type 1 (AT1) axis of the renin–angiotensin system (RAS), an essential process in maintaining circulatory homeostasis (
      • Alexandre J.
      • Cracowski J.L.
      • Richard V.
      • Bouhanick B.
      • Drugs C-wgotFSoPT
      Renin-angiotensin-aldosterone system and COVID-19 infection.
      ). AngII is a vasoconstrictive peptide catalysed from the proteolytic cleavage of angiotensin I by ACE in the lung that increases blood pressure (
      • Erdös E.G.
      Conversion of angiotensin I to angiotensin II.
      ). In coronavirus disease, ACE2 has been shown to be down-regulated in lung tissue, which has pathophysiological implications for infected patients. Although it has not been explicitly demonstrated for SARS-CoV-2, the mechanism of viral binding and internalization of ACE2 is similar to that of SARS-CoV and may even produce a more dramatic depletion given the increased affinity of SARS-CoV-2 spike protein for ACE2 (
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ,
      • Kuba K.
      • Imai Y.
      • Rao S.
      • Gao H.
      • Guo F.
      • Guan B.
      • et al.
      A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury.
      ,
      • Imai Y.
      • Kuba K.
      • Penninger J.M.
      The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice.
      ,
      • Wrapp D.
      • Wang N.
      • Corbett K.S.
      • Goldsmith J.A.
      • Hsieh C.-L.
      • Abiona O.
      • et al.
      Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.
      ). ACE2 is a well-characterized regulator of pulmonary vasodilation, postulated as a potential treatment for pulmonary hypertension (
      • Li G.
      • Liu Y.
      • Zhu Y.
      • Liu A.
      • Xu Y.
      • Li X.
      • et al.
      ACE2 activation confers endothelial protection and attenuates neointimal lesions in prevention of severe pulmonary arterial hypertension in rats.
      ).
      Interestingly, patients hospitalized with COVID-19 display features of pulmonary vascular dysregulation, and while ACE2 may be down-regulated in pulmonary tissue, patients experience increased vasodilatation as opposed to vasoconstriction. This would also appear discordant with the observed increase in circulating AngII. This article explores this phenomenon and postulates how despite the classical vasodilatory property of ACE2, its SARS-CoV-2-mediated down-regulation may have consequences beyond the RAS pathway that may shed light on this clinico-molecular discordance.

      COVID-19 pneumonia and pulmonary vasculopathy

      Thus far in the coronavirus pandemic, two distinct phases of COVID-19 acute respiratory distress syndrome (CARDS) have been observed: type H, a more classical acute respiratory distress syndrome picture, and type L (
      • Gattinoni L.
      • Chiumello D.
      • Rossi S.
      COVID-19 pneumonia: ARDS or not?.
      ,
      • Gattinoni L.
      • Chiumello D.
      • Caironi P.
      • Busana M.
      • Romitti F.
      • Brazzi L.
      • et al.
      COVID-19 pneumonia: different respiratory treatments for different phenotypes?.
      ). In CARDS type L, patients present with generally preserved lung mechanics with mild interstitial oedema evidenced by ground glass opacifications on computed tomography (CT) scan. COVID-19 patients may remain at type L and improve, or progress to type H (
      • Gattinoni L.
      • Chiumello D.
      • Caironi P.
      • Busana M.
      • Romitti F.
      • Brazzi L.
      • et al.
      COVID-19 pneumonia: different respiratory treatments for different phenotypes?.
      ). Type L patients present with profound hypoxaemia and show evidence of V/Q mismatch; a dilative pulmonary vasculopathy is observed, while alveolar ventilation is generally preserved with minimal alveolar oedema (Fig. 1) (
      • Gattinoni L.
      • Chiumello D.
      • Rossi S.
      COVID-19 pneumonia: ARDS or not?.
      ,
      • Gattinoni L.
      • Chiumello D.
      • Caironi P.
      • Busana M.
      • Romitti F.
      • Brazzi L.
      • et al.
      COVID-19 pneumonia: different respiratory treatments for different phenotypes?.
      ,
      • Marini J.J.
      • Gattinoni L.
      Management of COVID-19 Respiratory Distress.
      ). In terms of pulmonary physiology, excessive pulmonary vasodilation increases blood flow across the alveoli, resulting in a decrease in the red blood cell transit time required for gas exchange, which may account for the hypoxia in these patients evidenced by increased right-to-left venous admixture of over 50% (normally 4–10%) (
      • Gattinoni L.
      • Chiumello D.
      • Rossi S.
      COVID-19 pneumonia: ARDS or not?.
      ). Pulmonary vasodilatation and congestion are also important risk factors for pulmonary emboli, both of which are observed in COVID-19 patient autopsies (
      • Leisman D.E.
      • Deutschman C.S.
      • Legrand M.
      Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation.
      ).
      Fig. 1
      Fig. 1Alveolar changes in CARDS type L: (A) normal lung tissue; (B) lung tissue in CARDS type L; (C) lung tissue in CARDS type H.

      ACE2, angiotensin II, and pulmonary vasculopathy

      The clinical observation of pulmonary vasodilation in CARDS and the presence of significantly increased AngII in COVID-19 requires further investigation (
      • Gattinoni L.
      • Chiumello D.
      • Rossi S.
      COVID-19 pneumonia: ARDS or not?.
      ,
      • Liu Y.
      • Yang Y.
      • Zhang C.
      • Huang F.
      • Wang F.
      • Yuan J.
      • et al.
      Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.
      ). A current theory explaining this phenomenon involves the loss of hypoxic pulmonary vasoconstriction (HPV) (
      • Gattinoni L.
      • Chiumello D.
      • Rossi S.
      COVID-19 pneumonia: ARDS or not?.
      ). The effect of AngII on HPV has been controversial; despite its vasoconstrictive activity, AngII does not influence HPV (
      • Hubloue I.
      • Rondelet B.
      • Kerbaul F.
      • Biarent D.
      • Milani G.M.
      • Staroukine M.
      • et al.
      Endogenous angiotensin II in the regulation of hypoxic pulmonary vasoconstriction in anaesthetized dogs.
      ). Conversely, recombinant ACE2 has been shown to counter HPV, indicating that the enzyme’s down-regulation in a hypoxic patient should cause further vasoconstriction (
      • Kleinsasser A.
      • Pircher I.
      • Treml B.
      • Schwienbacher M.
      • Schuster M.
      • Janzek E.
      • et al.
      Recombinant angiotensin-converting enzyme 2 suppresses pulmonary vasoconstriction in acute hypoxia.
      ). Additionally, AngII is elevated in patients with pulmonary hypertension, which should, in theory, steer the pathophysiology of increased AngII signalling in COVID-19 towards a vasoconstrictive and pulmonary hypertensive phenotype (
      • Maron B.A.
      • Leopold J.A.
      The role of the renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (2013 Grover Conference series).
      ). Interestingly, the conversion of AngII to angiotensin-(1–7) may even be independent of ACE2 activity in mice, indicating that the effect of ACE2 down-regulation, AngII up-regulation, and pulmonary vasodilation in COVID-19 may require investigating these proteins beyond their counter-regulatory effects on vascular tone and even beyond vascular tissue (
      • Serfozo P.
      • Wysocki J.
      • Gulua G.
      • Schulze A.
      • Ye M.
      • Liu P.
      • et al.
      Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
      ).

      The immunovascular effects of ACE2 down-regulation and angiotensin II signalling

      While clinical data for COVID-19 are ever-increasing, one can extrapolate the immunovascular effects of ACE2 and AngII dysregulation from in vitro and in vivo data (Table 1).
      Table 1Effects of angiotensin-converting enzyme 2 (ACE2) down-regulation and angiotensin II (AngII) signalling on endothelial cells and macrophages.
      Effects of ACE2 down-regulationEffects of Angiotensin II signalling
      ExpressionMacrophagesReferencesEndothelial cellsReferencesMacrophagesReferencesEndothelial cellsReferences
      TNFaIncreased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      ,
      • Thatcher S.E.
      • Gupte M.
      • Hatch N.
      • Cassis L.A.
      Deficiency of ACE2 in Bone-Marrow-Derived Cells Increases Expression of TNF-α in Adipose Stromal Cells and Augments Glucose Intolerance in Obese C57BL/6 Mice.
      Increased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      Increased
      • Nakamura A.
      • Johns E.J.
      • Imaizumi A.
      • Yanagawa Y.
      • Kohsaka T.
      EFFECT OF β2-ADRENOCEPTOR ACTIVATION AND ANGIOTENSIN II ON TUMOUR NECROSIS FACTOR AND INTERLEUKIN 6 GENE TRANSCRIPTION IN THE RAT RENAL RESIDENT MACROPHAGE CELLS.
      ,
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      ,
      • Thatcher S.E.
      • Gupte M.
      • Hatch N.
      • Cassis L.A.
      Deficiency of ACE2 in Bone-Marrow-Derived Cells Increases Expression of TNF-α in Adipose Stromal Cells and Augments Glucose Intolerance in Obese C57BL/6 Mice.
      ,
      • Wu L.
      • Chen K.
      • Xiao J.
      • Xin J.
      • Zhang L.
      • Li X.
      • Ma K.
      Angiotensin II induces RAW264.7 macrophage polarization to the M1‑type through the connexin 43/NF‑κB pathway.
      Increased
      • Ruiz-Ortega M.
      • Ruperez M.
      • Lorenzo O.
      • Esteban V.
      • Blanco J.
      • Mezzano S.
      • et al.
      Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney.
      ,
      • Nakamura A.
      • Johns E.J.
      • Imaizumi A.
      • Yanagawa Y.
      • Kohsaka T.
      EFFECT OF β2-ADRENOCEPTOR ACTIVATION AND ANGIOTENSIN II ON TUMOUR NECROSIS FACTOR AND INTERLEUKIN 6 GENE TRANSCRIPTION IN THE RAT RENAL RESIDENT MACROPHAGE CELLS.
      MIFn/aIncreased
      • Zhong J.C.
      • Yu X.Y.
      • Lin Q.X.
      • Li X.H.
      • Huang X.Z.
      • Xiao D.Z.
      • et al.
      Enhanced angiotensin converting enzyme 2 regulates the insulin/Akt signalling pathway by blockade of macrophage migration inhibitory factor expression.
      n/aIncreased
      • Zhong J.C.
      • Yu X.Y.
      • Lin Q.X.
      • Li X.H.
      • Huang X.Z.
      • Xiao D.Z.
      • et al.
      Enhanced angiotensin converting enzyme 2 regulates the insulin/Akt signalling pathway by blockade of macrophage migration inhibitory factor expression.
      MCP1Increased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      Increased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      n/aIncreased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      Il-6Increased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      Increased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      Increased
      • Nakamura A.
      • Johns E.J.
      • Imaizumi A.
      • Yanagawa Y.
      • Kohsaka T.
      EFFECT OF β2-ADRENOCEPTOR ACTIVATION AND ANGIOTENSIN II ON TUMOUR NECROSIS FACTOR AND INTERLEUKIN 6 GENE TRANSCRIPTION IN THE RAT RENAL RESIDENT MACROPHAGE CELLS.
      ,
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      ,
      • Wu L.
      • Chen K.
      • Xiao J.
      • Xin J.
      • Zhang L.
      • Li X.
      • Ma K.
      Angiotensin II induces RAW264.7 macrophage polarization to the M1‑type through the connexin 43/NF‑κB pathway.
      Increased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      ,
      • Thatcher S.E.
      • Gupte M.
      • Hatch N.
      • Cassis L.A.
      Deficiency of ACE2 in Bone-Marrow-Derived Cells Increases Expression of TNF-α in Adipose Stromal Cells and Augments Glucose Intolerance in Obese C57BL/6 Mice.
      eNOSn/aDecreased
      • Zhong J.C.
      • Yu X.Y.
      • Lin Q.X.
      • Li X.H.
      • Huang X.Z.
      • Xiao D.Z.
      • et al.
      Enhanced angiotensin converting enzyme 2 regulates the insulin/Akt signalling pathway by blockade of macrophage migration inhibitory factor expression.
      ,
      • Rabelo L.A.
      • Todiras M.
      • Nunes-Souza V.
      • Qadri F.
      • Szijártó I.A.
      • Gollasch M.
      • et al.
      Genetic Deletion of ACE2 Induces Vascular Dysfunction in C57BL/6 Mice: Role of Nitric Oxide Imbalance and Oxidative Stress.
      n/aDecreased
      • Zhong J.C.
      • Yu X.Y.
      • Lin Q.X.
      • Li X.H.
      • Huang X.Z.
      • Xiao D.Z.
      • et al.
      Enhanced angiotensin converting enzyme 2 regulates the insulin/Akt signalling pathway by blockade of macrophage migration inhibitory factor expression.
      iNOSIncreased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      n/aIncreased
      • Nagareddy P.R.
      • Xia Z.
      • McNeill J.H.
      • MacLeod K.M.
      Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes.
      Increased
      • Vincent J.L.
      • Zhang H.
      • Szabo C.
      • Preiser J.C.
      Effects of nitric oxide in septic shock.
      MMP2/9Increased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      Increased
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      n/an/an/a
      eNOS, endothelial nitric oxide synthase; IL-6, interleukin 6; iNOS, inducible nitric oxide synthase; MCP1, monocyte chemoattractant protein 1; MIF, macrophage inhibitory factor; MMP2/9, matrix metalloproteinase 2/9; NA, not available; TNFα, tumour necrosis factor alpha.
      In cultured EAhy926 endothelial cells (ECs), ACE2 expression down-regulates macrophage migration inhibitory factor (MIF), a proinflammatory cytokine with implications for the pathogenesis of COVID-19 (
      • Zhong J.C.
      • Yu X.Y.
      • Lin Q.X.
      • Li X.H.
      • Huang X.Z.
      • Xiao D.Z.
      • et al.
      Enhanced angiotensin converting enzyme 2 regulates the insulin/Akt signalling pathway by blockade of macrophage migration inhibitory factor expression.
      ). Interestingly, AngII has been shown to increase MIF expression through AT1 signalling in ECs, and is known to be proinflammatory, inducing M1 macrophages; thus both the loss of ACE2 and the observed increase in AngII may bolster cytokine expression and macrophage activity in SARS-CoV-2 infection (
      • Zhong J.C.
      • Yu X.Y.
      • Lin Q.X.
      • Li X.H.
      • Huang X.Z.
      • Xiao D.Z.
      • et al.
      Enhanced angiotensin converting enzyme 2 regulates the insulin/Akt signalling pathway by blockade of macrophage migration inhibitory factor expression.
      ,
      • Ruiz-Ortega M.
      • Ruperez M.
      • Lorenzo O.
      • Esteban V.
      • Blanco J.
      • Mezzano S.
      • et al.
      Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney.
      ,
      • Nakamura A.
      • Johns E.J.
      • Imaizumi A.
      • Yanagawa Y.
      • Kohsaka T.
      EFFECT OF β2-ADRENOCEPTOR ACTIVATION AND ANGIOTENSIN II ON TUMOUR NECROSIS FACTOR AND INTERLEUKIN 6 GENE TRANSCRIPTION IN THE RAT RENAL RESIDENT MACROPHAGE CELLS.
      ). Moreover, ACE2 knockout mouse models have demonstrated significantly higher levels of interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP1), matrix metalloproteinases 2 and 9 (MMP2/9), and tumour necrosis factor alpha (TNFα) in ECs, which are only further exacerbated by atherosclerosis, which is a risk factor for COVID-19 morbidity (
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      ,
      • Bonow R.O.
      • Fonarow G.C.
      • O’Gara P.T.
      • Yancy C.W.
      Association of Coronavirus Disease 2019 (COVID-19) With Myocardial Injury and Mortality.
      ). Loss of ACE2 has also been shown to upregulate proinflammatory, vasodilative [Au?1] bradykinin signalling through the bradykinin B1 receptor (BKB1R), which also implicates the des-Arg bradykinin pathway in COVID-19 pulmonary vasodilation (
      • Sodhi C.P.
      • Wohlford-Lenane C.
      • Yamaguchi Y.
      • Prindle T.
      • Fulton W.B.
      • Wang S.
      • et al.
      Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg(9) bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration.
      ). ACE2 knockout ECs have also demonstrated increased responsiveness to TNFα, which leads to endothelial damage
      • Thomas M.C.
      • Pickering R.J.
      • Tsorotes D.
      • Koitka A.
      • Sheehy K.
      • Bernardi S.
      • et al.
      Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
      ). Another knockout study in bone marrow resulted in increased expression of the macrophage markers F4/80, as well as TNFα (
      • Thatcher S.E.
      • Gupte M.
      • Hatch N.
      • Cassis L.A.
      Deficiency of ACE2 in Bone-Marrow-Derived Cells Increases Expression of TNF-α in Adipose Stromal Cells and Augments Glucose Intolerance in Obese C57BL/6 Mice.
      ). A SARS-CoV-2-mediated down-regulation of ACE2 in macrophages may produce a similar TNFα-mediated proinflammatory, vasodilatory effect, which is further exacerbated by both ACE2 disinhibition and AngII-mediated enhancement of vascular MIF and MCP1 expression and TNFα reactivity.
      Interestingly, AngII, MIF, and TNFα are involved in vascular dysregulation and macrophage nitric oxide (NO) production, which implicates these molecules in CARDS pulmonary vasculopathy (
      • Zhong J.C.
      • Yu X.Y.
      • Lin Q.X.
      • Li X.H.
      • Huang X.Z.
      • Xiao D.Z.
      • et al.
      Enhanced angiotensin converting enzyme 2 regulates the insulin/Akt signalling pathway by blockade of macrophage migration inhibitory factor expression.
      ,
      • Riches D.W.
      • Chan E.D.
      • Winston B.W.
      TNF-alpha-induced regulation and signalling in macrophages.
      ,
      • Wu L.
      • Chen K.
      • Xiao J.
      • Xin J.
      • Zhang L.
      • Li X.
      • Ma K.
      Angiotensin II induces RAW264.7 macrophage polarization to the M1‑type through the connexin 43/NF‑κB pathway.
      ,
      • Nagareddy P.R.
      • Xia Z.
      • McNeill J.H.
      • MacLeod K.M.
      Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes.
      ). ACE2 deficiency has also been shown to increase vascular smooth muscle reactivity to NO, and while TNFα overall supresses EC nitric oxide synthase (eNOS) activity, it remains an important inducer of NO production in Th1 responding macrophages. Moreover, TNFα and its induction of nitric oxide synthase (iNOS) and NO have pivotal roles in inducing vasodilatory shock (
      • Fonseca S.G.
      • Romão P.R.
      • Figueiredo F.
      • Morais R.H.
      • Lima H.C.
      • Ferreira S.H.
      • et al.
      TNF-alpha mediates the induction of nitric oxide synthase in macrophages but not in neutrophils in experimental cutaneous leishmaniasis.
      ,
      • Rabelo L.A.
      • Todiras M.
      • Nunes-Souza V.
      • Qadri F.
      • Szijártó I.A.
      • Gollasch M.
      • et al.
      Genetic Deletion of ACE2 Induces Vascular Dysfunction in C57BL/6 Mice: Role of Nitric Oxide Imbalance and Oxidative Stress.
      ,
      • Vincent J.L.
      • Zhang H.
      • Szabo C.
      • Preiser J.C.
      Effects of nitric oxide in septic shock.
      ). This indicates that NO production in early COVID-19 disease by macrophages, combined with cytokine-mediated vascular injury potentiated by ACE2 down-regulation, increased AngII signalling, and viral EC lysis, may contribute to COVID-19 pulmonary vasculopathy (Fig. 2) (
      • Kodukula P.
      • Liu T.
      • Rooijen N.V.
      • Jager M.J.
      • Hendricks R.L.
      Macrophage control of herpes simplex virus type 1 replication in the peripheral nervous system.
      ,
      • Merad M.
      • Martin J.C.
      Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages.
      ). This immunovascular model of COVID-19 pathogenesis may also partially explain the effectiveness of immunosuppressive dexamethasone in COVID-19 patients requiring respiratory support (
      • Horby P.
      • Lim W.S.
      • Emberson J.
      • Mafham M.
      • Bell J.
      • Linsell L.
      • et al.
      Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report.
      ).
      Fig. 2
      Fig. 2Mechanism of angiotensin-converting enzyme 2 (ACE2) and angiotensin II (AngII) contribution to pulmonary vasculopathy.

      ACE inhibitors and angiotensin receptor blockade

      In the model presented, one cannot discuss the RAS system without addressing the effects of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in COVID-19. Due to elevated circulating AngII in COVID-19, one would assume that modulators of the RAS system could be beneficial to limit the inflammatory effects of AngII and may increase the expression of cytoprotective ACE2 (
      • Vaduganathan M.
      • Vardeny O.
      • Michel T.
      • McMurray J.J.V.
      • Pfeffer M.A.
      • Solomon S.D.
      Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19.
      ). In the immunovascular model presented, their use would be a double-edged sword, in that AT1 blockade or decreased AngII production would indeed decrease proinflammatory AngII signalling, however this may exacerbate the observed pulmonary vasodilation and worsen hypoxemia in CARDS type L. Therefore further studies assessing these drugs should distinguish these two types of coronaviral disease, as inflammation may play a larger role in CARDS type H (
      • Gattinoni L.
      • Chiumello D.
      • Caironi P.
      • Busana M.
      • Romitti F.
      • Brazzi L.
      • et al.
      COVID-19 pneumonia: different respiratory treatments for different phenotypes?.
      ). Lastly, there is both conflicting and insufficient evidence for the effects of ACEIs and ARBs on pulmonary ACE2 levels (
      • Vaduganathan M.
      • Vardeny O.
      • Michel T.
      • McMurray J.J.V.
      • Pfeffer M.A.
      • Solomon S.D.
      Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19.
      ). Assuming these drugs increase ACE2, as several studies indicate, the theoretical increase in membrane-bound ACE2 would be protective against pulmonary and vascular injury, however it would also provide more binding sites for new virions and may facilitate the spread of the infection (
      • Vaduganathan M.
      • Vardeny O.
      • Michel T.
      • McMurray J.J.V.
      • Pfeffer M.A.
      • Solomon S.D.
      Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19.
      ). Given the uncertainty in the literature and the possible risks and benefits of RAS modulation highlighted in this disease model, it is difficult to determine a precise role for RAS modulation in COVID-19 other than controlling important morbidity risk factors, namely hypertension and heart failure (
      • Vaduganathan M.
      • Vardeny O.
      • Michel T.
      • McMurray J.J.V.
      • Pfeffer M.A.
      • Solomon S.D.
      Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19.
      ).

      Conclusions

      SARS-CoV-2 is a novel coronavirus displaying unprecedented clinical presentations with unique pathophysiology. Here, an immunovascular theory is postulated for pulmonary vasculopathy from SARS-CoV-2-mediated ACE2 down-regulation, resulting in vasodilatory signalling loops between ACE2-deficient macrophages, ACE2-deficient vessels, and enhanced AngII signalling, mediated by MIF, TNFα, and iNOS. While trials are underway targeting these pathways in COVID-19 patients (TNFα: NCT04425538; MIF: NCT04429555; dexamethasone: NCT04381936), we call for further investigation into this phenomenon in the hopes of increasing the understanding of COVID-19 and its pathophysiology.

      Funding

      None.

      Ethical approval

      None.

      Conflict of interest

      The author declares no conflict of interest.

      Acknowledgements

      Figures created with BioRender.com.

      References

        • Alexandre J.
        • Cracowski J.L.
        • Richard V.
        • Bouhanick B.
        • Drugs C-wgotFSoPT
        Renin-angiotensin-aldosterone system and COVID-19 infection.
        Ann Endocrinol (Paris). 2020; 81: 63-67
        • Bonow R.O.
        • Fonarow G.C.
        • O’Gara P.T.
        • Yancy C.W.
        Association of Coronavirus Disease 2019 (COVID-19) With Myocardial Injury and Mortality.
        JAMA Cardiol. 2020; 5: 751-753
        • Erdös E.G.
        Conversion of angiotensin I to angiotensin II.
        Am J Med. 1976; 60: 749-759
        • Fonseca S.G.
        • Romão P.R.
        • Figueiredo F.
        • Morais R.H.
        • Lima H.C.
        • Ferreira S.H.
        • et al.
        TNF-alpha mediates the induction of nitric oxide synthase in macrophages but not in neutrophils in experimental cutaneous leishmaniasis.
        Eur J Immunol. 2003; 33: 2297-2306
        • Gattinoni L.
        • Chiumello D.
        • Rossi S.
        COVID-19 pneumonia: ARDS or not?.
        Critical Care. 2020; 24: 154
        • Gattinoni L.
        • Chiumello D.
        • Caironi P.
        • Busana M.
        • Romitti F.
        • Brazzi L.
        • et al.
        COVID-19 pneumonia: different respiratory treatments for different phenotypes?.
        Intensive Care Med. 2020; 46: 1099-1102
        • Hoffmann M.
        • Kleine-Weber H.
        • Schroeder S.
        • Kruger N.
        • Herrler T.
        • Erichsen S.
        • et al.
        SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.
        Cell. 2020; 181 (271-80 e8)
        • Horby P.
        • Lim W.S.
        • Emberson J.
        • Mafham M.
        • Bell J.
        • Linsell L.
        • et al.
        Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report.
        medRxiv. 2020; (2020.06.22.20137273)
        • Hubloue I.
        • Rondelet B.
        • Kerbaul F.
        • Biarent D.
        • Milani G.M.
        • Staroukine M.
        • et al.
        Endogenous angiotensin II in the regulation of hypoxic pulmonary vasoconstriction in anaesthetized dogs.
        Crit Care. 2004; 8 (R163-R71)
        • Imai Y.
        • Kuba K.
        • Penninger J.M.
        The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice.
        Exp Physiol. 2008; 93: 543-548
        • Kleinsasser A.
        • Pircher I.
        • Treml B.
        • Schwienbacher M.
        • Schuster M.
        • Janzek E.
        • et al.
        Recombinant angiotensin-converting enzyme 2 suppresses pulmonary vasoconstriction in acute hypoxia.
        Wilderness Environ Med. 2012; 23: 24-30
        • Kodukula P.
        • Liu T.
        • Rooijen N.V.
        • Jager M.J.
        • Hendricks R.L.
        Macrophage control of herpes simplex virus type 1 replication in the peripheral nervous system.
        J Immunol (Baltimore, Md: 1950). 1999; 162: 2895-2905
        • Kuba K.
        • Imai Y.
        • Rao S.
        • Gao H.
        • Guo F.
        • Guan B.
        • et al.
        A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury.
        Nature Med. 2005; 11: 875-879
        • Leisman D.E.
        • Deutschman C.S.
        • Legrand M.
        Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation.
        Intensive Care Med. 2020; 46: 1105-1108
        • Li G.
        • Liu Y.
        • Zhu Y.
        • Liu A.
        • Xu Y.
        • Li X.
        • et al.
        ACE2 activation confers endothelial protection and attenuates neointimal lesions in prevention of severe pulmonary arterial hypertension in rats.
        Lung. 2013; 191: 327-336
        • Liu Y.
        • Yang Y.
        • Zhang C.
        • Huang F.
        • Wang F.
        • Yuan J.
        • et al.
        Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.
        Sci China Life Sci. 2020; 63: 364-374
        • Marini J.J.
        • Gattinoni L.
        Management of COVID-19 Respiratory Distress.
        JAMA. 2020;
        • Maron B.A.
        • Leopold J.A.
        The role of the renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (2013 Grover Conference series).
        Pulm Circ. 2014; 4: 200-210
        • Merad M.
        • Martin J.C.
        Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages.
        Nat Rev Immunol. 2020; 20: 355-362
        • Nagareddy P.R.
        • Xia Z.
        • McNeill J.H.
        • MacLeod K.M.
        Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes.
        Am J Physiol Heart Circulatory Physiol. 2005; 289 (H2144-52)
        • Nakamura A.
        • Johns E.J.
        • Imaizumi A.
        • Yanagawa Y.
        • Kohsaka T.
        EFFECT OF β2-ADRENOCEPTOR ACTIVATION AND ANGIOTENSIN II ON TUMOUR NECROSIS FACTOR AND INTERLEUKIN 6 GENE TRANSCRIPTION IN THE RAT RENAL RESIDENT MACROPHAGE CELLS.
        Cytokine. 1999; 11: 759-765
        • Rabelo L.A.
        • Todiras M.
        • Nunes-Souza V.
        • Qadri F.
        • Szijártó I.A.
        • Gollasch M.
        • et al.
        Genetic Deletion of ACE2 Induces Vascular Dysfunction in C57BL/6 Mice: Role of Nitric Oxide Imbalance and Oxidative Stress.
        PloS one. 2016; 11 (e0150255-e)
        • Riches D.W.
        • Chan E.D.
        • Winston B.W.
        TNF-alpha-induced regulation and signalling in macrophages.
        Immunobiology. 1996; 195: 477-490
        • Ruiz-Ortega M.
        • Ruperez M.
        • Lorenzo O.
        • Esteban V.
        • Blanco J.
        • Mezzano S.
        • et al.
        Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney.
        Kidney Int. 2002; 62: S12-S22
        • Serfozo P.
        • Wysocki J.
        • Gulua G.
        • Schulze A.
        • Ye M.
        • Liu P.
        • et al.
        Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent.
        Hypertension (Dallas, Tex: 1979). 2020; 75: 173-182
        • Sodhi C.P.
        • Wohlford-Lenane C.
        • Yamaguchi Y.
        • Prindle T.
        • Fulton W.B.
        • Wang S.
        • et al.
        Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg(9) bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration.
        Am J Physiol Lung Cell Mol Physiol. 2018; 314: L17-l31
        • Thatcher S.E.
        • Gupte M.
        • Hatch N.
        • Cassis L.A.
        Deficiency of ACE2 in Bone-Marrow-Derived Cells Increases Expression of TNF-α in Adipose Stromal Cells and Augments Glucose Intolerance in Obese C57BL/6 Mice.
        Int J Hypertens. 2012; 2012762094
        • Thomas M.C.
        • Pickering R.J.
        • Tsorotes D.
        • Koitka A.
        • Sheehy K.
        • Bernardi S.
        • et al.
        Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse.
        Circulation Res. 2010; 107: 888-897
        • Vaduganathan M.
        • Vardeny O.
        • Michel T.
        • McMurray J.J.V.
        • Pfeffer M.A.
        • Solomon S.D.
        Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19.
        N Engl J Med. 2020; 382: 1653-1659
        • Verdecchia P.
        • Cavallini C.
        • Spanevello A.
        • Angeli F.
        The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
        Eur J Intern Med. 2020; 76: 14-20
        • Vincent J.L.
        • Zhang H.
        • Szabo C.
        • Preiser J.C.
        Effects of nitric oxide in septic shock.
        Am J Respir Crit Care Med. 2000; 161: 1781-1785
        • Wrapp D.
        • Wang N.
        • Corbett K.S.
        • Goldsmith J.A.
        • Hsieh C.-L.
        • Abiona O.
        • et al.
        Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.
        Science. 2020; 367: 1260
        • Wu L.
        • Chen K.
        • Xiao J.
        • Xin J.
        • Zhang L.
        • Li X.
        • Ma K.
        Angiotensin II induces RAW264.7 macrophage polarization to the M1‑type through the connexin 43/NF‑κB pathway.
        Mol Med Rep. 2020; 21: 2103-2112
        • Zhong J.C.
        • Yu X.Y.
        • Lin Q.X.
        • Li X.H.
        • Huang X.Z.
        • Xiao D.Z.
        • et al.
        Enhanced angiotensin converting enzyme 2 regulates the insulin/Akt signalling pathway by blockade of macrophage migration inhibitory factor expression.
        Br J Pharmacol. 2008; 153: 66-74