High pulsatility flow stimulates smooth muscle cell hypertrophy and contractile protein expression

Abstract

Proximal arterial stiffening is an important predictor of events in systemic and pulmonary hypertension, partly through its contribution to downstream vascular abnormalities. However, much remains undetermined regarding the mechanisms involved in the vascular changes induced by arterial stiffening. We therefore addressed the hypothesis that high pulsatility flow, caused by proximal arterial stiffening, induces downstream pulmonary artery endothelial cell (EC) dysfunction that in turn leads to phenotypic change of smooth muscle cells (SMCs). To test the hypothesis, we employed a model pulmonary circulation in which upstream compliance regulates the pulsatility of flow waves imposed onto a downstream vascular mimetic coculture composed of pulmonary ECs and SMCs. The effects of high pulsatility flow on SMCs were determined both in the presence and absence of ECs. In the presence of ECs, high pulsatility flow increased SMC size and expression of the contractile proteins, smooth muscle α-actin (SMA) and smooth muscle myosin heavy chain (SM-MHC), without affecting proliferation. In the absence of ECs, high pulsatility flow decreased SMC expression of SMA and SM-MHC, without affecting SMC size or proliferation. To identify the molecular signals involved in the EC-mediated SMC responses, mRNA and/or protein expression of vasoconstrictors [angiotensin-converting enzyme (ACE) and endothelin (ET)-1], vasodilator (eNOS), and growth factor (TGF-β1) in EC were examined. Results showed high pulsatility flow decreased eNOS and increased ACE, ET-1, and TGF-β1 expression. ACE inhibition with ramiprilat, ET-1 receptor inhibition with bosentan, and treatment with the vasodilator bradykinin prevented flow-induced, EC-dependent SMC changes. In conclusion, high pulsatility flow stimulated SMC hypertrophy and contractile protein expression by altering EC production of vasoactive mediators and cytokines, supporting the idea of a coupling between proximal vascular stiffening, flow pulsatility, and downstream vascular function.

Microvessel Mechanobiology in Pulmonary Arterial Hypertension

“…3 Amplified pulse wave transmission to the distal vasculature, also a result of proximal arterial stiffening, increases shear stress on the endothelium and results in an inflammatory response that drives further distal vascular remodeling, vasoconstriction, ECM production, and subsequent loss of distal PAC, further elevating mPAP. 18,19 Understanding the mechanisms that drive alterations in distal arterial compliance may allow for new drug targets capable of preventing disease progression in the early stages of development and help break the cycle of positive feedback that partially makes PAH so intractable to traditional therapies.…”

Vascular Stiffening in Pulmonary Hypertension: Cause or Consequence? (2013 Grover Conference Series)

“…52,88,95 Conversely, stiffer vessels absorb a smaller fraction of the volume from each cardiac stroke, resulting in a substantial increase in pressure, which leads to relatively high pulse pressures 96,97 and high wall shear stress as well as high flow and pressure pulsatility in downstream vessels. 52 Our data support the idea that these flow and pressure changes are sensed by the endothelial cells (ECs) lining the more downstream vessels and then transduced into biochemical signals that influence vascular remodeling.…”

“…We have shown that, with the same mean flow stresses (the static flow component), FPI, reflecting the dynamic component of flow mechanical stresses, determines distal PA cell responses. [86][87][88] We showed that, compared to low-pulsatility flow (LPF; FPI ¼ 0.2-0.5), HPF (FPI > 1) induced proinflammatory responses in the vascular endothelium. As illustrated in Figure 3, by imposing flows with varied FPIs on a monolayer of microvascular bovine PAECs, HPF with a physiological mean flow WSS (10-14 dyne/cm 2 ) consistently enhanced distal PAEC expression of proinflammatory molecules at the gene and protein levels, leading to in- Figure 3.…”

The Role of Wall Shear Stress in the Assessment of Right Ventricle Hydraulic Workload

“…16 An elevated resistance in the distal arteries causes a pressure increase in the large proximal vasculature, leading to proximal arterial remodeling in the form of increased arterial stiffness and thickness. This compromises the proximal vasculature's role as a hydraulic damper to the distal vessels, 17,18 causing distal endothelial cells to be exposed to nonphysiological pulse pressure and initiating a destructive cycle. Proximal arterial stiffening is also believed to affect wave reflections and has been shown to contribute to cardiac workload in the systemic circulation.…”