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. 2023 Mar 8;15(3):706.
doi: 10.3390/v15030706.

COVID-19 and Pulmonary Angiogenesis: The Possible Role of Hypoxia and Hyperinflammation in the Overexpression of Proteins Involved in Alveolar Vascular Dysfunction

Anna Flavia Ribeiro Santos Miggiolaro  1 , Felipe Paes Gomes da Silva  2 , David Batista Wiedmer  2 , Thiago Mateus Godoy  2 , Nicolas Henrique Borges  2 , Giulia Werner Piper  2 , Alessandro G G Oricil  2 , Carolline Konzen Klein  2 , Elisa Carolina Hlatchuk  3 , Júlio César H Dagostini  3 , Mariana Collete  1 , Mayara Pezzini Arantes  1 , Raissa C D'Amico  1 , Anderson A Dutra  1 , Marina Luise Viola de Azevedo  1 , Lucia de Noronha  2
Affiliations

COVID-19 and Pulmonary Angiogenesis: The Possible Role of Hypoxia and Hyperinflammation in the Overexpression of Proteins Involved in Alveolar Vascular Dysfunction

Anna Flavia Ribeiro Santos Miggiolaro et al. Viruses. .

Abstract

COVID-19 has been considered a vascular disease, and inflammation, intravascular coagulation, and consequent thrombosis may be associated with endothelial dysfunction. These changes, in addition to hypoxia, may be responsible for pathological angiogenesis. This research investigated the impact of COVID-19 on vascular function by analyzing post-mortem lung samples from 24 COVID-19 patients, 10 H1N1pdm09 patients, and 11 controls. We evaluated, through the immunohistochemistry technique, the tissue immunoexpressions of biomarkers involved in endothelial dysfunction, microthrombosis, and angiogenesis (ICAM-1, ANGPT-2, and IL-6, IL-1β, vWF, PAI-1, CTNNB-1, GJA-1, VEGF, VEGFR-1, NF-kB, TNF-α and HIF-1α), along with the histopathological presence of microthrombosis, endothelial activation, and vascular layer hypertrophy. Clinical data from patients were also observed. The results showed that COVID-19 was associated with increased immunoexpression of biomarkers involved in endothelial dysfunction, microthrombosis, and angiogenesis compared to the H1N1 and CONTROL groups. Microthrombosis and vascular layer hypertrophy were found to be more prevalent in COVID-19 patients. This study concluded that immunothrombosis and angiogenesis might play a key role in COVID-19 progression and outcome, particularly in patients who die from the disease.

Keywords: SARS-CoV-2; angiogenesis; endothelial dysfunction; immunohistochemistry; microthrombi.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Compares the levels of ICAM-1 (A), ANGPT-2 (B), IL-6 (C), and IL-1β (D) proteins in tissue samples from COVID-19 patients versus control and H1N1pdm09 patients. The data is presented as a graphical representation of the comparison between the groups and the corresponding immunohistochemistry staining images. The difference between the groups was determined using the non-parametric Kruskal-Wallis test. When there was significance, the Mann-Whitney test was applied in the two-by-two comparison, with significance (*) indicated by a p-value less than 0.05.
Figure 2
Figure 2
Comparison of the levels of vWF (A) and PAI-1 (B) proteins in tissue samples from COVID-19 patients versus control and H1N1pdm09 patients. The data is presented as a graphical representation of the group comparison and the corresponding immunohistochemistry staining images. The difference between the three groups was determined using the non-parametric Kruskal-Wallis test. When the three groups were significant, the Mann-Whitney test was applied in the two-by-two comparison, with significance (*) indicated by a p-value less than 0.05.
Figure 3
Figure 3
Comparison of the levels of CTNNB-1 (A), GJA-1 (B), VEGF (C), VEGFR-1 (D), NF-kB (E), and TNF-α (F) proteins in tissue samples from COVID-19 patients versus control and H1N1pdm09 patients. The data is presented as a graphical representation of the comparison between the groups and the corresponding immunohistochemistry staining images. The difference between the groups was determined using the non-parametric Kruskal-Wallis test. When there was significance, the Mann-Whitney test was applied in the two-by-two comparison, with significance (*) indicated by a p-value less than 0.05.
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Grants and funding

This work was supported by productivity research level 2 of the National Council for Scientific and Technological Development (CNPq) and BRDE-PUCPR (Banco Regional de Desenvolvimento do Extremo Sul).