Am J Physiol Heart Circ Physiol. 2026 Apr 29. doi: 10.1152/ajpheart.00095.2026. Online ahead of print.
ABSTRACT
Hypertension and arterial stiffening are major contributors to cardiovascular disease and are closely linked to vascular inflammation. Activation of the renin-angiotensin-aldosterone system promotes unfavorable immune responses that lead to vascular inflammation and remodeling; however, the exact molecular mediators connecting immune activation to arterial stiffening remain poorly understood. Transglutaminase 2 (TG2) is a multifunctional enzyme involved in extracellular matrix remodeling and inflammatory signaling, expressed in both vascular and immune cells. We hypothesized that TG2 in myeloid cells facilitates Angiotensin II (Ang II)-induced hypertension and aortic stiffening by driving detrimental immune responses. Female mice with myeloid-specific deletion of TG2 (MyTG2KO) and littermate controls were infused with Ang II for 14 days. Ang II infusion resulted in elevated systolic blood pressure, aortic stiffness, and vascular collagen deposition in control mice, whereas these responses were markedly reduced in MyTG2KO mice. Deleting myeloid TG2 lowered vascular expression of proinflammatory markers and circulating cytokines. Flow cytometry analysis showed that Ang II was associated with disruption of immune balance, characterized by decreased regulatory T cells (Tregs) and increased Th17 cells; these changes were attenuated in MyTG2KO mice. Consistent with these results, TG2-deficient macrophages promoted Treg development, suppressed Th17 polarization, and decreased CD8+T cell cytotoxicity in co-culture experiments. These findings highlight myeloid TG2 as an important contributor to Ang II-related immune imbalance, vascular inflammation, aortic stiffening, and hypertension. Targeting TG2 in myeloid cells could be a novel strategy to reduce immune-driven vascular remodeling in hypertensive cardiovascular disease.
PMID:42053807 | DOI:10.1152/ajpheart.00095.2026