Abstract 12185: Hypoxia Exacerbates Flow-Induced Vascular Remodeling via CXCL12/CXCR4 Pathway
Tim Klouda, Savas Tsiki, Tiffany Liu, Yunhye Kim, Gary A Visner, Mark Puder, Benjamin Raby, Ke Yuan- Physiology (medical)
- Cardiology and Cardiovascular Medicine
Intro: Patients with congenital heart disease are at risk of developing pulmonary arterial hypertension (PAH-CHD) due to increased blood flow and exposure to hypoxia (Hx). We aimed to establish a“two-hit” mouse model of pulmonary hypertension (PH) combining increased blood flow via left pneumonectomy (LP) and Hx ( Fig 1a ). Our objective was to investigate the pathogenesis of flow-induced vascular remodeling and elucidate the underlying mechanism mediated by smooth muscle cells (SMCs) through the CXCL12/CXCR4 pathway.
Hypothesis: We hypothesize SMCs contribute to flow-induced vascular remodeling by upregulating the Cxcl12/Cxcr4 pathway.
Methods: Mice underwent LP followed by 3 weeks of Hx(LP/Hx). PH was evaluated by measuring right ventricular systolic pressure (RVSP) and Fulton Index. Whole lung lobes and precision cut lung slices underwent tissue clearing, immunofluorescence staining and advanced microscopy. SMCs were isolated using Dynabeads and Cxcl12 signaling measured by RT-qPCR. Tissue samples from patients with PAH-CHD (ventricular septal defect) were stained for CXCL12.
Results: LP/Hx mice demonstrated severe PH compared to Hx controls, as evidenced by increased RVSP (41 vs 33mm Hg), right ventricle hypertrophy (FI: 40 vs 32%) and RV dysfunction ( Fig 1b ). SMCs from LP/Hx mice exhibited an 8.6-fold increase in Cxcl12 expression compared to controls, with Hx and LP alone showing 5-fold and 2-fold increases, respectively. Advanced microscopy revealed excessive remodeling of distal arterioles in LP/Hx mice ( Fig 1c ). Furthermore, CXCL12 expression was upregulated in SMCs of patients with PAH-CHD compared to controls.
Conclusion: Our study, using a novel mouse model combining increased blood flow and hypoxia, demonstrated that upregulation of Cxcl12 in SMCs and ECs contributes to flow-induced vascular remodeling. This model has the potential to serve as a pre-clinical model for studying the pathology of PAH-CHD and exploring therapeutic interventions.