Abstract 021: Blood Pressure Magnitude as a Modulator of Perivascular Adipose Tissue Fibrotic Response

Hypertension (HTN) induces vascular remodeling, characterized by fibrosis. Collagen is the main extracellular matrix component produced during vascular remodeling. Fibrosis is well characterized in the vascular tunicas but not in the outermost layer of blood vessels: the perivascular adipose tissue (PVAT). PVAT Adipocytes are maintained by adipogenesis of progenitor cells (APC) expressing PDGFRα. APC are an undifferentiated population that also can generate fibrogenic lineages. It is unclear whether HTN induces PVAT remodeling and if APC drive this process. We hypothesize that increased blood pressure promotes PVAT APC differentiation towards a fibrogenic fate leading to increased collagen deposition. Mice (PDGFRa-CreERT2-tdT n=12) were used to trace APC (PDGFRα + ). A blood pressure gradient was induced using thoracic aortic coarctation using an O-ring (coarct), creating a hypertensive (upstream: up) and hypotensive (downstream: down) gradient within the same mouse. This allowed for determining fibrogenic remodeling in response to an elevated pressure by using the animal as its own control. Sham underwent surgery without an O-ring. Blood pressure was measured by telemetry under anesthesia. Blood flow velocity was measured with Doppler ultrasound (mm/sec; reported as a ratio up:down). After 8 weeks, thoracic aorta (up and down)+PVAT was collected and stained with Masson’s trichromic or Anti-RFP-AF568 for imaging with second harmonic generation (SHG). Image analyzed with QuPath v0.4.4. Collagen area was calculated as % of blue or SHG signal from PVAT area. Collagen-producing APC (tdT + SHG + ) and non-APC (tdT - SHG + ) were quantified in PVAT (% from total nuclei). Results are mean±SEM. Coarctation created a 19 mmHg mean arterial pressure gradient. A higher blood flow ratio was found in coarct (2.05±0.18 vs sham 1.04±0.03). Collagen area in PVAT was higher up (10.6±2.6) vs. down (4.3±0.6) in coarct, but without differences in sham up (4.06±1.3) vs. down (3.9±0.9) (P<0.02). Similarly, collagen measured by SHG area was higher in coarct PVAT up (9.3±2.2) vs. down (4.8±1.1) (P=0.2), while no differences in sham up (7.1±1.1) vs. down (4.5±2.1). Collagen-producing APC (SHG + ) were higher in up (15.4±4.3) vs. down (10±2.2) (P=0.5) when compared to sham animals up (12.8±2.9) vs. down (16.5±2.2). These findings indicate that APC may drive PVAT remodeling within PVAT. Future studies will investigate the role of mechanosensation in PVAT fibrosis.