Abstract 522: Shear Stress Quantification and Regulation of Endothelial Cell Dysfunction in Models of Pulmonary Arterial Hypertension
Pulmonary endothelial dysfunction may play a significant role in the progression of Pulmonary Arterial Hypertension (PH). We hypothesized that
wall shear stress (SS) is reduced in the proximal pulmonary arteries (PAs) of PH patients compared to control subjects,
reduced SS contributes to pulmonary endothelial cell dysfunction and PH progression.
Methods: A combined MRI and computational fluid dynamics (CFD) approach was used to quantify in vivo SS in subject-specific PA models of PH and control subjects. These SS values were applied to confluent human pulmonary artery endothelial cells (HPAEC) in culture using a cone-plate viscometer device for 1, 6, and 24 hours. HPAEC exposed to control and PH SS levels for 24h were then exposed to hypoxic conditions (1% O2) for 1h. RT-PCR was used to quantify gene expression of normal EC function (eNOS, NOQ-1, HSP90) and markers of inflammation (PECAM, MCP-1). Expression of sheared samples was normalized to age and time-matched, non-sheared samples.
Results: Image-based CFD results showed significantly (p <0.001) lower time-averaged central PA SS in PH patients (3.03 +/- 0.43 dynes/cm2) than controls (17.78 +/- 1.38 dynes/cm2). In vitro, at certain time points, markers of normal EC function were significantly (p < 0.05) downregulated, while inflammatory markers were upregulated, with PH, compared to control, SS levels. With hypoxia, significant differences in expression were observed between the two shear levels for all genes (figure⇓).
SS is reduced in the proximal PAs of PH patients compared to control subjects, and
these levels of SS regulate HPAEC transcriptional events related to vascular remodeling.