04 February 2019 by Jingsi Zhao

Blood-borne microRNA-210 promotes pulmonary hypertension via extracellular endothelial delivery and interstitial lung macrophage expansion

Background:

The hypoxia-inducible miR-210 promotes pulmonary hypertension by repressing the iron-sulfur assembly proteins ISCU1/2 in PAECs. Recently, it has been proposed that the vascular pathobiology of microRNAs may rely on their transport in the blood to the vascular bed. However, whether the development of PH depends critically on blood-borne transport of pathogenic microRNAs remains unanswered.

Results:

To interrogate the role of blood-borne miR-210 in PH pathogenesis, we utilized an in vivo parabiosis platform in the context of wildtype (WT) and miR-210-null (KO) mice, followed by chronic exposure to hypoxia (10% oxygen) for 3 weeks. While miR-210 was not detectable in KOKO pairs, extracellular miR-210 in plasma was robustly expressed in KOs of WT-KO pairs (4789±795.2 copy numbers/μL plasma, n=5). In those KOs, intracellular miR-210 was observed in CD31-positive lung ECs at substantial levels (26.6±3.284 copy numbers/10 pg RNA, n=10). By in situ staining of miR-210, ISCU1/2, and CD31, miR-210 expression in KOs of WT-KO pairs was detected specifically in pulmonary arteriolar endothelium, accompanied by a reciprocal decrease in ISCU1/2 expression (n=6). Furthermore, by FACS, an expansion of CD64/CD11b-positive interstitial lung macrophages was observed in KOs of WT-KO pairs versus KO-KO partners (5176.7 vs. 2132.5/mg tissue, n=3, p<0.05). By RT-qPCR, isolated interstitial lung macrophages were found to express miR-210 in KOs of WT-KO (341.5±79 copy numbers/ng RNA, n=3).

Importantly, KOs of WT-KO developed higher RVSP versus KO-KO partners (30.8±1.2 vs. 26.4±0.5 mmHg, n=7, p<0.01), along with increased RV remodeling by RV mass/body weight ratio (1.048±0.0327 vs. 0.9195±0.04704 mg/g, n=13, p<0.05) and increased pulmonary arteriolar muscularization.

Conclusion:

Blood-borne transport of miR-210 with consequent uptake into pulmonary vascular endothelial cells and vascular expansion of miR-210-expression interstitial lung macrophages promote PH in vivo. These findings reveal a multi-level, RNA-mediated system of anatomic crosstalk, advancing the characterization of this disease as a truly systemic condition.

About the author


profile picture of Jingsi Zhao

Jingsi Zhao

Research Lab Technician

University of Pittsburgh

United States

Key Contributors

Jingsi Zhao 1, Jonathan Florentin 1,#, Thomas Bertero 2,#, Yi-Yin Tai 1,#, Ying Tang 1, Vinny Negi 1, Partha Dutta 1, and Stephen Y. Chan 1 : (1) Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA (2) University Côte d’Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France. # denotes equal contribution by these authors.


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