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Funding Statement: Support was provided solely from
institutional and/or departmental sources
Conflicts of Interest: The authors declare no competing
interests
Dear Editor,
We enjoyed the article by Cardot-Leccia et al. demonstrating apoptosis
and pericyte loss (PL) in alveolar capillaries in COVID + lung [1].
This PL, with capillary and venular wall thickening in the area of DAD
and in normal lung, without inflammation, and with intact epithelium and
endothelium, is remarkable; we believe it supports our
“Epithelial-Endothelial Cross-Talk” hypothesis [2] with additional
players ─ pericytes.
As SARS-CoV-2 has minimal cytopathic effects and low immunogenicity
[2], we believe that direct epithelial cell-injury is not the usual
mechanism by which COVID-19 progresses to ARDS. Instead, we believe,
“epithelial-endothelial-pericyte” cross-talk following SARS-CoV-2
infection of pulmonary alveolar epithelial cells (AEC) results in
indirect activation of endothelial cells (EC) giving rise to a
procoagulant-proinflammatory and profibrotic-phenotype similar to that
seen in indirect-ARDS (Supplementary Fig. 1).
Based on our model, SARS-CoV-2 infection of AEC leads to downregulation
of ACE2 and increased gene-expression of IL-6 and TNF-α in AEC via
SARS-CoV2-ACE2-TACE and SARS-CoV2-PRR-NFκB interactions
[3]. IL6-sIL-6Rα, IL-1β, and
sTNF-α are then released on the luminal and abluminal sides of
epithelial cells. IL6-sIL6R-1α and sTNF-α subsequently act on the EC
from the basal side and increases the gene and protein expression of ACE
and AT1R in the EC. Increased ACE activity on the apical side of EC
increases local production of Ang II and AT1R upregulation results in
increased Ang II-AT1R activity. Ang II-AT1R overactivity then increases
TACE-TNF-α and ACE-AT1R expression and downregulates ACE2 in the EC,
establishing a positive feed-forward pathway [3]. Increased ACE/ACE2
balance along with upregulated IL-6 and TNF-α mediated actions may
stimulate a cascade of pathways, resulting in vasoconstriction, PL,
endothelial barrier-disruption and cytokine-release syndrome (Fig. 1).
Direct action of Ang II-AT1R on pericytes can increase cytosolic
calcium, resulting in pericyte contraction and capillary
vasoconstriction. Ang II-AT1R-PKC pathway-mediated closure of
intercellular gap-junctions can lead to pericyte-pericyte and
pericyte-endothelial uncoupling [4]. Upregulation of Ang-2 and VEGF
activity by Ang II-AT1R-MAPK pathways antagonizes protective Tie2-Ang-1
system resulting in PL, EC apoptosis and pathological angiogenesis.
Increased TACE-mediated ectodomain shedding of ACE2 and Ang II-mediated
reduction of ACE2 expression may relieve repression of integrin
signaling rendering pericyte more susceptible to the Ang-2 and in turn,
lead to the pericyte apoptosis by the Ang-2/integrin signaling pathway
[5]. Ang II/AT1R/ROS regulated phosphorylation of PDGFRβ on
pericytes may play a role in the pathobiology. Upregulation of ET-1
causes inappropriate pericyte contraction and reduced vessel diameter.
Our model explains the stage of PL when endothelium and epithelium are
intact, perivascular inflammation is minimal and SARS-CoV2 infection of
pericytes via ACE2 (even if present) seems unlikely. PL may be the first
morphological change progressing to EC loss, leaving behind
non-perfusing and constricted acellular capillaries. Capillary
non-perfusion can stimulate intussusceptive and sprouting angiogenesis,
which might explain findings wedge-shaped areas of reduced perfusion
with dilatation of proximal vasculature as well as extensive
angiogenesis in COVID-19.
PL and endothelial barrier-disruption can expedite pulmonary epithelium
cell-injury and epithelial disruption, allowing hematogenous spread of
infection. Notably, previous reports on SARS-CoV2 endothelitis have
confirmed SARS-CoV2 directly infecting the EC [1].