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Implication of in vivo circulating fibrocytes ablation in experimental pulmonary hypertension murine model
Author(s) -
Nikam Vandana S.,
Nikam Sandeep,
Sydykov Akyl,
Ahlbrecht Katrin,
Morty Rory E.,
Seeger Werner,
Voswinckel Robert
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15025
Subject(s) - ganciclovir , fibrocyte , pulmonary hypertension , transgene , pathology , genetic enhancement , medicine , in vivo , genetically modified mouse , hypoxia (environmental) , vascular remodelling in the embryo , biology , immunology , chemistry , virus , gene , human cytomegalovirus , biochemistry , microbiology and biotechnology , organic chemistry , oxygen
Background and Purpose Recruitment and involvement of bone‐/blood‐derived circulating fibrocytes (CF) in the promotion of fibrotic tissue remodelling processes have been shown. However, their direct contribution to pathological changes is not clear. The present study investigates the causal role of CF in the pathogenesis of pulmonary hypertension (PH). Experimental Approach For selective ablation of CF, we applied the suicidal gene strategy with herpes simplex virus thymidine kinase (HSV‐TK) and ganciclovir. The transgenic mice were generated, having HSV‐TK‐GFP transgene under the collagen 1 promoter. To selectively target CF, HSV‐TK‐GFP + bone marrow transplanted into irradiated wild type mice. These chimera mice were subjected to hypoxia for PH induction and ganciclovir for CF ablation. Key Results In vivo CF ablation reduced right ventricular hypertrophy and vascular remodelling with reduced total collagen content. We quantified the CF recruited in the perivascular area and arterial wall of small pulmonary arteries. There was significant recruitment of CF in the lung in response to hypoxia. The characterization of CF showed the expression of CD45 and collagen1 (GFP) along with α‐smooth muscle actin (αSMA). Conclusion and Implications Our data demonstrated that CF ablation has a potential impact on right ventricular hypertrophy and vascular remodelling in the setting of experimental pulmonary hypertension induced by hypoxia. The beneficial effects may be related to the direct contribution of fibrocytes or its paracrine effect on other resident cell types. Thus, clinical manipulation of CF may represent a novel therapeutic approach to ameliorate the disease state in pulmonary hypertension.