Adult mammalian cardiomyocytes have minimal cell cycle capacity, which leads to poor regeneration after cardiac injury such as myocardial infarction. Many positive regulators of cardiomyocyte cell cycle and cardioprotective signals have been identified, but extracellular signals that suppress cardiomyocyte proliferation are poorly understood. We profiled receptors enriched in postnatal cardiomyocytes, and found that very-low-density-lipoprotein receptor (Vldlr) inhibits neonatal cardiomyocyte cell cycle. Paradoxically, Reelin, the well-known Vldlr ligand, expressed in cardiac Schwann cells and lymphatic endothelial cells, promotes neonatal cardiomyocyte proliferation. Thrombospondin1 (TSP-1), another ligand of Vldlr highly expressed in adult heart, was then found to inhibit cardiomyocyte proliferation through Vldlr, and may contribute to Vldlr’s overall repression on proliferation. Mechanistically, Rac1 and subsequent Yap phosphorylation and nucleus translocation mediate the regulation of the cardiomyocyte cell cycle by TSP-1/Reelin-Vldlr signaling. Importantly, Reln mutant neonatal mice displayed impaired cardiomyocyte proliferation and cardiac regeneration after apical resection, while cardiac-specific Thbs1 deletion and cardiomyocyte-specific Vldlr deletion promote cardiomyocyte proliferation and are cardioprotective after myocardial infarction. Our results identified a novel role of Vldlr in consolidating extracellular signals to regulate cardiomyocyte cell cycle activity and survival, and the overall suppressive TSP-1-Vldlr signal may contribute to the poor cardiac repair capacity of adult mammals.

成年哺乳动物心肌细胞的细胞周期能力极低，这导致心肌梗塞等心脏损伤后再生能力较差。心肌细胞细胞周期和心脏保护信号的许多正调节因子已被识别，但抑制心肌细胞增殖的细胞外信号却知之甚少。我们对出生后心肌细胞中富集的受体进行了分析，发现极低密度脂蛋白受体（Vldlr）抑制新生儿心肌细胞周期。矛盾的是，众所周知的 Vldlr 配体 Reelin 在心脏雪旺细胞和淋巴内皮细胞中表达，可促进新生儿心肌细胞增殖。血小板反应蛋白 1 (TSP-1) 是 Vldlr 在成人心脏中高表达的另一种配体，随后发现它可以通过 Vldlr 抑制心肌细胞增殖，并可能有助于 Vldlr 对增殖的整体抑制。从机制上讲，Rac1 和随后的 Yap 磷酸化和核易位通过 TSP-1/Reelin-Vldlr 信号传导介导心肌细胞周期的调节。重要的是， Reln突变的新生小鼠在心尖切除后表现出心肌细胞增殖和心脏再生受损，而心脏特异性Thbs1缺失和心肌细胞特异性Vldlr缺失促进心肌细胞增殖并在心肌梗死后具有心脏保护作用。我们的结果确定了Vldlr在巩固细胞外信号以调节心肌细胞细胞周期活性和存活方面的新作用，并且整体抑制 TSP-1-Vldlr 信号可能导致成年哺乳动物心脏修复能力差。