Targeting lymphatic endothelial CXCR4 to promote cardiac lymphangiogenesis and lymphatic function after myocardial infarction
Abstract Body: Background: Heart failure remains a leading cause of death worldwide, with limited therapeutic options to restore cardiac function after myocardial infarction (MI). Therapeutic lymphangiogenesis, including VEGF-C delivery, promotes cardiac lymphatic growth and improves cardiac recovery after MI, but the molecular mechanisms regulating this process remain incompletely understood. We recently reported that the chemokine receptor CXCR4 is required for lymphatic vessel development and that CXCL12/CXCR4 signaling in lymphatic endothelial cells (LECs) promotes lymphangiogenesis by enhancing VEGF-C mediated VEGFR3/PI3K/AKT signaling. However, whether CXCR4 regulates cardiac lymphangiogenesis after MI has not been explored. We hypothesized that LEC-specific CXCR4 is required for endogenous and therapeutic lymphangiogenesis following MI. Methods and Results: Using LEC-specific CXCR4 knockout mice, we found that loss of CXCR4 markedly impaired cardiac lymphangiogenesis after MI, accompanied by reduced LEC proliferation. CXCR4 deficiency also worsened post-infarction cardiac remodeling, as demonstrated by impaired echocardiographic function and increased cardiac fibrosis compared with control mice. In addition, immunostaining revealed increased macrophage accumulation in the infarcted hearts of CXCR4 mutant mice, suggesting impaired inflammatory resolution. Together, these findings support an essential role for LEC-CXCR4 in the lymphatic response to cardiac injury. Conclusions: LEC-specific CXCR4 is a critical regulator of cardiac lymphangiogenesis and cardiac repair after MI. These findings identify CXCR4 as an important component of lymphatic-mediated tissue repair and a potential therapeutic target for ischemic heart disease. Ongoing studies are focused on defining the mechanisms by which CXCR4/CXCL12 signaling regulates post-MI lymphangiogenesis and determining whether targeting this pathway can enhance cardiac recovery after injury.
Do, Long
(
Temple University
, Philadelphia , Pennsylvania , United States )
Delgado, Esteban
(
Temple University
, Philadelphia , Pennsylvania , United States )
Flynn, Liam
(
Temple University
, Philadelphia , Pennsylvania , United States )
Fallouh, Sarah
(
Temple University
, Philadelphia , Pennsylvania , United States )
Pang, Jingjing
(
Temple University
, Philadelphia , Pennsylvania , United States )
Liu, Hongxia
(
Temple University
, Philadelphia , Pennsylvania , United States )
Gao, Erhe
(
Temple University
, Philadelphia , Pennsylvania , United States )
Liu, Xiaolei
(
Temple University
, Philadelphia , Pennsylvania , United States )
Author Disclosures:
Long Do:DO NOT have relevant financial relationships
| Esteban Delgado:DO NOT have relevant financial relationships
| Liam Flynn:No Answer
| Sarah Fallouh:No Answer
| Jingjing Pang:DO NOT have relevant financial relationships
| Hongxia Liu:No Answer
| Erhe Gao:No Answer
| Xiaolei Liu:DO NOT have relevant financial relationships