Given the insufficient regeneration capacity of the adult heart, cardiovascular diseases lead to permanent loss of cardiomyocytes. Loss of these contractile components of the heart in addition to their replacement with non-contractile fibrotic tissue leads to reduced cardiac function, which is not sufficient to supply the circulation need of the body and progresses to heart failure. When the adult heart is exposed to pressure overload for example as a result of aortic valve stenosis, cardiomyocytes hypertrophy and fibroblasts enhance their proliferation, differentiate into myofibroblasts, and secrete collagen. This leads to cardiac hypertrophy and generation of interstitial and perivascular fibrosis in the heart, which consequently leads to stiffness of the myocardium and reduces contractility. In contrast to the adult heart, we have recently shown that neonatal mice at postnatal day 1 (P1), are able to adapt to pressure overload by going through hyperplasia instead of hypertrophy. This capacity, however, is lost 7 days after birth when cardiomyocytes exit the cell cycle. Thus, pressure overload at P7 leads to cardiomyocyte hypertrophy and deterioration of cardiac function. Interestingly, fibroblasts also respond differently to pressure overload in P1 compared to P7 and adults. 14 days of pressure overload in P1 mice in contrast to P7 and adult hearts did not lead to fibrosis or an increase in the number of fibroblasts in the heart. Here, we investigated different responses of fibroblasts at P1 and P7 to pressure overload and their contribution to the adaptive response of the heart at P1.  
RNA bulk sequencing of the fibroblasts shortly after induction of pressure overload in P1 and P7 mice revealed different responses in terms of gene expression pattern. P1 fibroblasts overexpressed genes related to gene ontology biological processes related to enhancing angiogenesis and immune response, while P7 fibroblasts upregulated genes related to cell cycle and proliferation. These differences in gene pattern could clearly explain the reason for the increased number of fibroblasts and interstitial fibrosis in the heart after P7 injury. More in-depth analysis of fibroblasts at P1 revealed upregulation of many secreted factors, with known and unknown roles in enhancing cardiomyocyte proliferation, angiogenesis, and immune response. However, upregulated genes related to secreted factors in P7 fibroblasts were in general less than in P1. We selected some unique upregulated P1 fibroblast secreted factors with unknown roles in cardiomyocyte proliferation and angiogenesis to investigate their effect on cardiomyocyte and endothelial cells. For this purpose, we treated primary isolated murine cardiomyocytes, primary endothelial cells and human umbilical vein endothelial cells (HUVEC) with the selected fibroblast factors and performed a variety of proliferation, apoptosis, cell migration and angiogenesis assays in vitro. This study revealed that selected factors from P1 fibroblasts can enhance proliferation rate and survival of cardiomyocytes and endothelial cells in vitro. In addition, we discovered their role in enhancing angiogenesis and tube formation of HUVEC in vitro. Together, our study revealed pro-proliferative, pro-survival and pro-angiogenic effects of P1 fibroblasts secretom in response to pressure overload, which can contribute to the overall adaptive response of the neonatal mouse heart to pressure overload.