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Inhibition of lymphatic lymphangiogenesis is involved in cardiac edema and cardiac remodeling after ischemic injury or pressure overload. However, whether lymphatic vessel integrity is disrupted during angiotensin II\u2010 (Ang II\u2010) induced cardiac remodeling remains to be investigated. In this study, cardiac remodeling models were established by Ang II (1000\u2009ng\/kg\/min) in VEGFR\u20103 knockdown (Lyve\u20101<jats:sup>Cre<\/jats:sup> VEGFR\u20103<jats:sup>f\/\u2212<\/jats:sup>) and wild\u2010type (VEGFR\u20103<jats:sup>f\/f<\/jats:sup>) littermates. Our results indicated that Ang II infusion not only induced cardiac lymphangiogenesis and upregulation of VEGF\u2010C and VEGFR\u20103 expression in the time\u2010dependent manner but also enhanced proteasome activity, MKP5 and VE\u2010cadherin degradation, p38 MAPK activation, and lymphatic vessel hyperpermeability. Moreover, VEGFR\u20103 knockdown significantly inhibited cardiac lymphangiogenesis in mice, resulting in exacerbation of tissue edema, hypertrophy, fibrosis superoxide production, inflammation, and heart failure (HF). Conversely, administration of epoxomicin (a selective proteasome inhibitor) markedly mitigated Ang II\u2010induced cardiac edema, remodeling, and dysfunction; upregulated MKP5 and VE\u2010cadherin expression; inactivated p38 MAPK; and reduced lymphatic vessel hyperpermeability in WT mice, indicating that inhibition of proteasome activity is required to maintain lymphatic endothelial cell (LEC) integrity. Our results show that both cardiac lymphangiogenesis and lymphatic barrier hyperpermeability are implicated in Ang II\u2010induced adaptive hypertrophic remodeling and dysfunction. Proteasome\u2010mediated hyperpermeability of LEC junctions plays a predominant role in the development of cardiac remodeling. Selective stimulation of lymphangiogenesis or inhibition of proteasome activity may be a potential therapeutic option for treating hypertension\u2010induced cardiac remodeling.<\/jats:p>","DOI":"10.1155\/2022\/5044046","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T22:50:10Z","timestamp":1645224610000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Angiotensin II Induces Cardiac Edema and Hypertrophic Remodeling through Lymphatic\u2010Dependent 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