Immunohistochemical profile of HIF-1α, VEGF-A, VEGFR2 and MMP9 proteins in tegumentary leishmaniasis

Fraga, Carlos Alberto de Carvalho; Oliveira, Marcos Vinícius Macedo de; Alves, Lucas Rodrigues; Viana, Agostinho Gonçalves; Sousa, Adriana Alkmin de; Carvalho, Sílvio Fernando Guimarães; De-Paula, Alfredo Maurício Batista; Botelho, Ana Cristina de Carvalho; Guimarães, André Luiz Sena

doi:10.1590/s0365-05962012000500006

Cited by 13 publications

(18 citation statements)

References 29 publications

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“…We found that macrophages from infected mice were also the predominant cell type expressing HIF-1␣, with HIF-1␣ and VEGF-A displaying similar kinetics, thus strengthening the link between these two molecules during L. major infection. These findings are relevant to human leishmaniasis because human lesions also express VEGF-A and HIF-1␣, along with dilated vessels, corroborating our observations in the mouse model (15,22). In addition, we show that mice with deficient ARNT/HIF signaling in myeloid cells exhibit decreased VEGF-A production and enhanced immunopathology during L. major infection.…”

Section: Discussionsupporting

confidence: 89%

Leishmania Infection Induces Macrophage Vascular Endothelial Growth Factor A Production in an ARNT/HIF-Dependent Manner

et al. 2019

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Cutaneous leishmaniasis is characterized by vascular remodeling. Following infection with Leishmania parasites, the vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 (VEGFR-2) signaling pathway mediates lymphangiogenesis, which is critical for lesion resolution. Therefore, we investigated the cellular and molecular mediators involved in VEGF-A/VEGFR-2 signaling using a murine model of infection. We found that macrophages are the predominant cell type expressing VEGF-A during Leishmania major infection. Given that Leishmania parasites activate hypoxia-inducible factor 1α (HIF-1α) and this transcription factor can drive VEGF-A expression, we analyzed the expression of HIF-1α during infection. We showed that macrophages were also the major cell type expressing HIF-1α during infection and that infection-induced VEGF-A production is mediated by ARNT/HIF activation. Furthermore, mice deficient in myeloid ARNT/HIF signaling exhibited larger lesions without differences in parasite numbers. These data show that L. major infection induces macrophage VEGF-A production in an ARNT/HIF-dependent manner and suggest that ARNT/HIF signaling may limit inflammation by promoting VEGF-A production and, thus, lymphangiogenesis during infection.

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Section: Discussionsupporting

confidence: 89%

Leishmania Infection Induces Macrophage Vascular Endothelial Growth Factor A Production in an ARNT/HIF-Dependent Manner

et al. 2019

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“…Infection also increased EC proliferation and the levels of VEGF-A and VEGFR-2. These findings are relevant to human leishmaniasis, as VEGF-A and VEGFR-2 are expressed in leishmanial lesions from humans along with dilated vessels, corroborating our findings in the mouse model (34). To determine if VEGF-A/VEGFR-2 signaling contributes to pathogen control or the severity of disease, infected mice were given VEGFR-2 blocking antibodies, which specifically decreased the percentage of proliferating LECs and exacerbated pathology.…”

Section: Discussionsupporting

confidence: 89%

Leishmania major Infection–Induced VEGF-A/VEGFR-2 Signaling Promotes Lymphangiogenesis That Controls Disease

Weinkopff

Konradt

Christian

et al. 2016

The Journal of Immunology

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Cutaneous leishmaniasis causes a spectrum of diseases from self-healing to severe non-healing lesions. Defining the factors contributing to lesion resolution may help in developing new therapies for those patients with chronic disease. We found that infection with Leishmania major increases the expression of vascular endothelial growth factor-A (VEGF-A) and vascular endothelial growth factor receptor-2 (VEGFR-2), and is associated with significant changes in the blood and lymphatic vasculature at the site of infection. Antibody blockade of VEGFR-2 during infection led to a reduction in lymphatic endothelial cell proliferation and simultaneously increased lesion size without altering the parasite burden. These data show that L. major infection initiates enhanced VEGF-A/VEGFR-2 signaling, and suggest that VEGFR-2-dependent lymphangiogenesis is a mechanism that restricts tissue inflammation in leishmaniasis.

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“…The pathogenic mechanisms leading to necrosis during CL are not well elucidated. Likely, this process is multifactorial, including vessel obliteration induced by vasculitis,1,29 killing of macrophages and epithelial cells expressing Leishmania antigen, and tissue injury by the inflammatory response 30–32. It is known that metalloproteinase (MMP) genes are highly expressed in the tissue of CL patients and that monocytes secrete high levels of MMP-9 33–35.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Histopathologic Features in Patients in the Early and Late Phases of Cutaneous Leishmaniasis

Saldanha¹,

Queiroz²,

Machado³

et al. 2017

Am J Trop Med Hyg

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Cutaneous leishmaniasis (CL), characterized by an ulcerated lesion, is the most common clinical form of human leishmaniasis. Before the ulcer develops, patients infected with Leishmania (Viannia) braziliensis present a small papule at the site of the sandfly bite, referred to as early cutaneous leishmaniasis (E-CL). Two to four weeks later the typical ulcer develops, which is considered here as late CL (L-CL). Although there is a great deal known about T-cell responses in patients with L-CL, there is little information about the in situ inflammatory response in E-CL. Histological sections of skin biopsies from 15 E-CL and 28 L-CL patients were stained by hematoxilin and eosin to measure the area infiltrated by cells, as well as tissue necrosis. Leishmania braziliensis amastigotes, CD4+, CD8+, CD20+, and CD68+ cells were identified and quantified by immunohistochemistry. The number of amastigotes in E-CL was higher than in L-CL, and the inflammation area was larger in classical ulcers than in E-CL. There was no relationship between the number of parasites and magnitude of the inflammation area, or with the lesion size. However, there was a direct correlation between the number of macrophages and the lesion size in E-CL, and between the number of macrophages and necrotic area throughout the course of the disease. These positive correlations suggest that macrophages are directly involved in the pathology of L. braziliensis–induced lesions.

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Immunohistochemical profile of HIF-1α, VEGF-A, VEGFR2 and MMP9 proteins in tegumentary leishmaniasis

Cited by 13 publications

References 29 publications

Leishmania Infection Induces Macrophage Vascular Endothelial Growth Factor A Production in an ARNT/HIF-Dependent Manner

Leishmania Infection Induces Macrophage Vascular Endothelial Growth Factor A Production in an ARNT/HIF-Dependent Manner

Leishmania major Infection–Induced VEGF-A/VEGFR-2 Signaling Promotes Lymphangiogenesis That Controls Disease

Characterization of the Histopathologic Features in Patients in the Early and Late Phases of Cutaneous Leishmaniasis

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