Perivascular adipose tissue in hypoxia-induced pulmonary hypertension promotes vascular stiffening by releasing adipsin and complement factors that activate macrophages and drive matrix remodeling.
Does perivascular adipose tissue-mediated complement activation promote vascular remodeling in hypoxia-induced pulmonary hypertension?
Perivascular adipose tissue acts as an immune hub in pulmonary hypertension, driving proximal pulmonary artery stiffening through adipsin-mediated complement activation and extracellular matrix remodeling.
Abstract Background Vascular stiffness predicts outcomes in systemic and pulmonary hypertension (PH) and reflects extracellular matrix (ECM) remodeling. Our proteomic studies in a hypoxia-induced PH calf model revealed early matrisome changes and robust upregulation of complement factors, most prominently in the main pulmonary artery (MPA), and we have previously established that complement is a potent driver of immune-vascular crosstalk in pulmonary vascular disease. Perivascular adipose tissue (PVAT) has emerged as a key source of adipsin (complement factor D) and complement C3, fueling alternative pathway activation and vascular inflammation. We hypothesized that in hypoxic PH, PVAT surrounding the main PA promotes stiffening by releasing adipsin, which activates complement and immune cells (macrophages and neutrophils), leading to ECM remodeling through collagen crosslinking and protease induction. Methods Vascular stiffness and collagen and elastin organization and immune cell infiltration were assessed in human MPAs and hypoxia-exposed calf/rat MPAs by 2-dimensional stress-strain testing, trichrome and Verhoeff-Van Gieson (VVG) staining, and immunofluorescence. Neutrophil elastase levels in MPA were determined by immunohistology staining. Gene expressions of cytokines, chemokines, and complement factors were measured in PA wall cells, PVAT, and other fat depots. Conditioned media (CM) from these fat depots was applied to bone marrow derived macrophages (BMDMs). Results Human, bovine and rat PH-MPAs showed marked changes in vascular stiffening in response to hypoxia, in addition to collagen accumulation, elastin degradation, and immune infiltration. PVAT from PH animals exhibited increased Ccl2, adipsin, C3, and S100As compared to controls. CM from PH-PVAT robustly activated BMDMs, upregulating complement receptors and profibrotic/ECM-remodeling genes IL-1β, TGFβ1, LOX, TGM2, and MMP2/9, whereas subcutaneous fat CM had smaller effects. Neutrophil elastase, which is important for elastin degradation, is increased in PH-MPAs compared to controls. Conclusions Perivascular adipose tissue is an immune hub in PH, with adipsin-driven complement activation amplifying immune cell responses and ECM remodeling, thereby contributing to proximal PA stiffening. This abstract is funded by: NIH/NHLBI P01HL152961, DOD PR191774 #W81XWH2010249
Li et al. (Fri,) conducted a other in Pulmonary hypertension. Hypoxia vs. Controls was evaluated on Vascular stiffness, collagen and elastin organization, and immune cell infiltration. Perivascular adipose tissue in hypoxia-induced pulmonary hypertension promotes vascular stiffening by releasing adipsin and complement factors that activate macrophages and drive matrix remodeling.