Early Life Stress Reprograms Bone Marrow Myeloid Progenitors via beta 2-adrenergic Signaling

Early life stress (ELS) orchestrates long-term changes in immune cell function and contributes to cardiovascular disease (CVD) risk, but the underlying mechanisms remain elusive. Previous work from our lab using flow cytometry demonstrated that adult mice subjected to maternal separation with early weaning (MSEW) exhibit expanded aortic macrophage populations, which, when mitigated by a CSF1R antagonist, normalize the elevated pulse wave velocity (a measure of future CVD risk) observed in MSEW mice. RNA sequencing of the isolated aorta revealed a unique profile of CSF1R-positive mature macrophages in the MSEW aorta, with increased expression of atherosclerotic-associated genes and trafficking associated genes. Whether these changes originate from the reprogramming of bone marrow progenitors is unknown. Chronic stress elevates sympathetic activity, increasing beta 2-adrenergic receptor stimulation on hematopoietic progenitors. We hypothesized that beta 2-adrenergic signaling through epigenetic modifications predisposes MSEW monocytes toward a pro-inflammatory phenotype that persists into adulthood and contributes to an imbalance of tissue macrophages. To assess adrenergic contributions, MSEW and normally reared (NR) mice received 2 mg/kg intraperitoneal injections of the selective β2-adrenergic inverse agonist ICI 118551 HCl or vehicle (0.9% saline) for ten days prior to bone marrow isolation at 12 weeks of age. Bone marrow cells (n=5 per group) were cultured with M-CSF for seven days and stimulated with 10 ng/mL LPS for 16 hours. ICI 118551 HCl treatment significantly reduced CSF1R expression (4.08 +/- 0.84 vs. 1.69 +/- 0.36; p = 0.01), MHCII expression (25.81 +/- 0.82 vs. 20.61 +/- 1.07; p = 0.008), and TNF production (3.20 +/- 0.96 vs. 1.18 +/- 0.28; p = 0.03), indicating that beta 2-adrenergic signaling modulates progenitor activation and myeloid maturation in MSEW mice. IL-4 production was not significantly altered (p > 0.05). To assess epigenetic modifications and their contribution to MSEW monocyte function, we used single-cell analysis of MSEW vs NR (n=2 each) aorta and analyzed after clustering by monocyte lineage. There was upregulation of epigenetic regulators Hdac10 and Hdac1, a trending increase in Hdac9, and elevated SETD2, consistent with epigenetic reprogramming. Collectively, these findings support a model in which ELS reprograms bone marrow progenitors via beta 2-adrenergic signaling, and epigenetic mechanisms promote persistent alterations in vascular macrophage populations, contributing to adult vascular dysfunction. Future studies will look at beta 2-adrenergic receptor abundance in MSEW vs NR bone marrow myeloid progenitors as well as epigenetic changes to these progenitors prior to seeding the vasculature. These results highlight that the link between ELS and long-term cardiovascular risk driven by aortic macrophages, may originate from β2-adrenergic signaling in the bone marrow. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.