CCL28 contributes to angiogenesis and cardiac repair by CCR10+ endothelial cells after myocardial infarction

Secretome-based therapies targeting angiogenesis are promising in ischemic heart disease (IHD). The effects of Chemokine C-C motif ligand (CCL) 28 on IHD remain unclear. This study investigated the role of CCL28 in angiogenesis in IHD. The myocardial infarction (MI) and hindlimb ischemia (HI) models were constructed on male wild-type and CCL28-knockout mice. AAV9-TIE1-sh-CCR10 induced endothelial specific CCR10 deficiency in mice by tail vein injection. Recombinant CCL28 protein was used to treat MI and HI in wild-type and db/db mice. Serum levels of CCL28 were evaluated in a cohort of 416 consecutive chronic total occlusions (CTO) patients. The upregulated CCL28/ C-C motif receptor (CCR)10 axis was observed in myocardial and hindlimb ischemia. Additionally, CCL28 was mainly secreted by macrophages and CCR10 was highly expressed in endothelial cells (ECs). Compared to CCR10- ECs, CCR10+ ECs exhibited robust proangiogenic capacity, which are induced by CCL28 through the CCR10/ERK/SOX5 positive feedback signaling. Deletion of CCL28 results in impaired angiogenesis in the ischemic models while the use of recombinant CCL28 protein has therapeutic potential for myocardial and hindlimb ischemia, including in diabetes. Endothelial specific CCR10 deficiency impairs angiogenesis and blocks the therapeutic effect of rCCL28 in the myocardial and hindlimb ischemia. Serum CCL28 levels exhibited the predictive effect on coronary collateral vessels (CCV) in CTO patients. CCR10+ endothelial cells (ECs) are characterized with the enhanced proangiogenic capacity and beneficial for angiogenesis. CCL28 promotes angiogenesis by increasing CCR10+ ECs via the CCR10/ERK/SOX5 positive feedback signaling. This study highlights the angiogenic role of CCL28 and recombinant CCL28 protein might be a potential therapeutic option to attenuate myocardial and hindlimb ischemia, including in diabetes. Overall design: RNA-seq was performed on CD45-CD31+ ECs magnetic bead sorted from WT and Ccl28-KO mice