Vanishing vessels aboding pulmonary disease: a role for VEGFR2

Botros, Liza; Vonk‐Noordegraaf, Anton; Aman, Jurjan

doi:10.1183/13993003.00326-2020

Cited by 3 publications

(2 citation statements)

References 21 publications

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“…The SU5416 emphysema model (17) posits that the promotion of EC apoptosis via blockade of VEGF/VEGFR2 signaling induces lung alveolar microvascular damage, followed by pneumocyte death. Importantly, VEGFR2 loss-of-function mutation was recently uncovered as a cause for emphysema and pulmonary hypertension in humans (47), strengthening SU5416-induced emphysema as a clinically relevant model (48). Our data show that loss or gain of endothelial Hif-2a expression respectively exacerbates or prevents SU5416-induced emphysema; these results indicate that HIF-2a protects ECs from VEGFR2 inhibition-induced cellular apoptosis.…”

Section: Discussionsupporting

confidence: 51%

Endothelial HIF-2α as a Key Endogenous Mediator Preventing Emphysema

Pasupneti

Tian

et al. 2020

Am J Respir Crit Care Med

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Rationale: Endothelial injury may provoke emphysema, but molecular pathways of disease development require further discernment. Emphysematous lungs exhibit decreased expression of HIF-2a (hypoxia-inducible factor-2a)-regulated genes, and tobacco smoke decreases pulmonary HIF-2a concentrations. These findings suggest that decreased HIF-2a expression is important in the development of emphysema.Objectives: The objective of this study was to evaluate the roles of endothelial-cell (EC) HIF-2a in the pathogenesis of emphysema in mice.Methods: Mouse lungs were examined for emphysema after either the loss or the overexpression of EC Hif-2a. In addition, SU5416, a VEGFR2 inhibitor, was used to induce emphysema. Lungs were evaluated for HGF (hepatocyte growth factor), a protein involved in alveolar development and homeostasis. Lungs from patients with emphysema were measured for endothelial HIF-2a expression.Measurements and Main Results: EC Hif-2a deletion resulted in emphysema in association with fewer ECs and pericytes. After SU5416 exposure, EC Hif-2a-knockout mice developed more severe emphysema, whereas EC Hif-2a-overexpressing mice were protected. EC Hif-2a-knockout mice demonstrated lower levels of HGF. Human emphysema lung samples exhibited reduced EC HIF-2a expression.Conclusions: Here, we demonstrate a unique protective role for pulmonary endothelial HIF-2a and how decreased expression of this endogenous factor causes emphysema; its pivotal protective function is suggested by its ability to overcome VEGF antagonism. HIF-2a may maintain alveolar architecture by promoting vascular survival and associated HGF production. In summary, HIF-2a may be a key endogenous factor that prevents the development of emphysema, and its upregulation has the potential to foster lung health in at-risk patients.

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Section: Discussionsupporting

confidence: 51%

Endothelial HIF-2α as a Key Endogenous Mediator Preventing Emphysema

Pasupneti

Tian

et al. 2020

Am J Respir Crit Care Med

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“…These disease pairs include COPD and TIA, PAD and Alzheimer's disease, and CKD and DM. It is known that COPD involves a dropout of alveolar microvasculature, 44 , 45 and COPD does increase the risk of stroke. 46 These results suggest that lymphatic derangements accompany microvascular disease in these conditions.…”

Section: Discussionmentioning

confidence: 99%

Exploring disease interrelationships in patients with lymphatic disorders: A single center retrospective experience

Rockson

Zhou

Zhao

et al. 2022

Clinical & Translational Med

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Background:The lymphatic contribution to the circulation is of paramount importance in regulating fluid homeostasis, immune cell trafficking/activation and lipid metabolism. In comparison to the blood vasculature, the impact of the lymphatics has been underappreciated, both in health and disease, likely due to a less well-delineated anatomy and function. Emerging data suggest that lymphatic dysfunction can be pivotal in the initiation and development of a variety of diseases across broad organ systems. Understanding the clinical associations between lymphatic dysfunction and non-lymphatic morbidity provides valuable evidence for future investigations and may foster the discovery of novel biomarkers and therapies. Methods:We retrospectively analysed the electronic medical records of 724 patients referred to the Stanford Center for Lymphatic and Venous Disorders.Patients with an established lymphatic diagnosis were assigned to groups of secondary lymphoedema, lipoedema or primary lymphovascular disease. Individuals found to have no lymphatic disorder were served as the non-lymphatic controls. The prevalence of comorbid conditions was enumerated. Pairwise cooccurrence pattern analyses, validated by Jaccard similarity tests, was utilised to investigate disease-disease interrelationships. Results: Comorbidity analyses underscored the expected relationship between the presence of secondary lymphoedema and those diseases that damage the lymphatics. Cardiovascular conditions were common in all lymphatic subgroups. Additionally, statistically significant alteration of disease-disease interrelationships was noted in all three lymphatic categories when compared to the control population.

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