Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension

eLife

Shoh Asano¹  Terri A Swanson²  Casey Ritenour²  Arun Shipstone³  Magalie Boucher⁴  Xian Chen⁴  Jincheng Pang⁴  Andrew Robertson⁴  Rachel J Roth Flach⁵  Furong Sun⁵  William C Sessa⁵  Brianna LaViolette⁶  Steven Kreuser⁷  Youngwook Ahn⁷  Hanna Sobon⁸  Teresa Cunio⁸  Michael W Nagle⁸  Sabra D Al-Harthy⁸  Katherine Hales⁸  LouJin Song⁸  Frank Voigt⁹ 

[1] Acceleron Pharma, Cambridge, United States;Drug Safety Research & Development, Pfizer Inc, Groton, United States;Eisai Inc, Cambridge, United States;Comparative Medicine, Pfizer Inc, Cambridge, United States;Drug Safety Research & Development, Pfizer Inc, Groton, United States;Early Clinical Development, Pfizer Inc, Cambridge, United States;Inflammation and Immunology Research Unit, Pfizer Inc, Cambridge, United States;Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States;Target Sciences, Emerging Science and Innovation, Pfizer Inc, Cambridge, United States;

关键词: lymphatic;    endothelial;    cardiac dysfunction;    inflammation;    hypertension;    fibrosis;   

DOI  :  10.7554/eLife.58376

来源: DOAJ

【 摘 要 】

The lymphatic vasculature is involved in the pathogenesis of acute cardiac injuries, but little is known about its role in chronic cardiac dysfunction. Here, we demonstrate that angiotensin II infusion induced cardiac inflammation and fibrosis at 1 week and caused cardiac dysfunction and impaired lymphatic transport at 6 weeks in mice, while co-administration of VEGFCc156s improved these parameters. To identify novel mechanisms underlying this protection, RNA sequencing analysis in distinct cell populations revealed that VEGFCc156s specifically modulated angiotensin II-induced inflammatory responses in cardiac and peripheral lymphatic endothelial cells. Furthermore, telemetry studies showed that while angiotensin II increased blood pressure acutely in all animals, VEGFCc156s-treated animals displayed a delayed systemic reduction in blood pressure independent of alterations in angiotensin II-mediated aortic stiffness. Overall, these results demonstrate that VEGFCc156s had a multifaceted therapeutic effect to prevent angiotensin II-induced cardiac dysfunction by improving cardiac lymphatic function, alleviating fibrosis and inflammation, and ameliorating hypertension.

【 授权许可】

Unknown