High Pulsatility Flow Induces Adhesion Molecule and Cytokine mRNA Expression in Distal Pulmonary Artery Endothelial Cells.

Li, M; Scott, Devon; Shanders, R; Stenmark, K.R.; Tan, Wei

doi:10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a2347

Cited by 29 publications

(47 citation statements)

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“…Besides the steady laminar and disturbed flows that are commonly studied in the literature, there is evidence that the pulsatility imposed on the laminar flow due to heart beats may also contribute to the regulation of vascular cell functions (37,38). In the present study the effects of PS with a significant forwarding direction (12 ± 4 dynes/ cm 2 ) in modulating miR expression was studied, and the miR modulation was related to mRNA expression by using bioinformatics analyses.…”

Section: Discussionmentioning

confidence: 91%

Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth

Wang

Garmire

Young

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

158

132

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MicroRNAs (miRs) can regulate many cellular functions, but their roles in regulating responses of vascular endothelial cells (ECs) to mechanical stimuli remain unexplored. We hypothesize that the physiological responses of ECs are regulated by not only mRNA and protein signaling networks, but also expression of the corresponding miRs. EC growth arrest induced by pulsatile shear (PS) flow is an important feature for flow regulation of ECs. miR profiling showed that 21 miRs are differentially expressed (8 up-and 13 downregulated) in response to 24-h PS as compared to static condition (ST). The mRNA expression profile indicates EC growth arrest under 24-h PS. Analysis of differentially expressed miRs yielded 68 predicted mRNA targets that overlapped with results of microarray mRNA profiling. Functional analysis of miR profile indicates that the cell cycle network is highly regulated. The upregulation of miR-23b and miR-27b was found to correlate with the PS-induced EC growth arrest. Inhibition of miR-23b using antagomir-23b oligonucleotide (AM23b) reversed the PSinduced E2F1 reduction and retinoblastoma (Rb) hypophosphorylation and attenuated the PS-induced G1/G0 arrest. Antagomir AM27b regulated E2F1 expression, but did not affect Rb and growth arrest. Our findings indicate that PS suppresses EC proliferation through the regulation of miR-23b and provide insights into the role of miRs in mechanotransduction.cell cycle | shear | bioinformatics | gene regulation | mechanotransduction H emodynamic forces, e.g., stretch and shear stress, act constantly on the vascular endothelial cells (ECs) to modulate EC signaling, gene expression, and physiological functions (1). Atherosclerotic lesions in the arterial tree are found mainly at branch points, where blood flow is disturbed with a limited forwarding direction, but are generally spared at the straight parts of the arterial tree, where the flow is laminar with a large forwarding direction (2). Exposure of ECs to 24 h of steady laminar shear flow at 12 dyn/cm 2 (approximating the hemodynamic force in straight parts of arteries) leads to antiproliferative (3) and antiinflammatory (4) responses. In contrast, ECs exposed to disturbed flow, mimicking the hemodynamic force at branch points, exhibit opposite responses (5, 6). The laminar shear-induced EC growth arrest involves the expression of CDK inhibitors (e.g., p21 cip , p27 kip ), tumor suppressor p53, and retinoblastoma (Rb) hypophosphorylation (3, 7). Whereas there is considerable knowledge on mechanotransduction at protein and mRNA levels, there is little information on the role of microRNAs (miRs) in this process.miRs are small noncoding RNAs (∼21-25 nucleotides) that regulate gene expression by binding to target mRNAs to cause their degradation or translational repression (8). It is estimated that miRs regulate ∼30% of human protein-coding genes. More than 800 miRs have been identified in the human genome and registered in the Sanger miRBase. These small RNAs provide a powerful mechanism for posttranscriptional cont...

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Section: Discussionmentioning

confidence: 91%

Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth

Wang

Garmire

Young

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

158

132

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“…Both pulsatile flow (Li et al, 2009) and laminar shear stress (Goettsch et al, 2008) have been reported to increase VEGF expression; however, the effect of shear stress on isoform distribution has not been examined. We show that HUVECs grown under static culture express all three major VEGF isoforms, with VEGF121 the predominant (54%) and VEGF189 the least abundant (10%) form.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro studies demonstrate that biomechanical stimuli, such as cyclic stretch, cause increased VEGF expression by vascular SMCs (Quinn et al, 2002;Mata-Greenwood et al, 2005), as well as other cell types (Gruden et al, 1997;Seko et al, 1999b;Seko et al, 1999a;Muratore et al, 2000;Motokawa et al, 2005) including ECs (Suzuma et al, 2001;Zheng et al, 2001). More recently, fluid shear stress has been implicated in the upregulation of VEGF-A gene expression (Parmar et al, 2006;Thi et al, 2007;Goettsch et al, 2008;Li et al, 2009) although the role and relevance of shear-stress-induced VEGF expression has yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Role of shear-stress-induced VEGF expression in endothelial cell survival

Paz

Walshe

Leach

et al. 2012

Journal of Cell Science

193

175

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SummaryVascular endothelial growth factor (VEGF) plays a crucial role in developmental and pathological angiogenesis. Expression of VEGF in quiescent adult tissue suggests a potential role in the maintenance of mature blood vessels. We demonstrate, using a Vegf-lacZ reporter mouse model, that VEGF is expressed by arterial but not by venous or capillary endothelial cells (ECs) in vivo. Using an in vitro model, we show that arterial shear stress of human umbilical vein ECs (HUVECs) decreases apoptosis and increases VEGF expression, which is mediated by the induction of Krüppel-like factor 2 (KLF2). Additionally, shear stress stimulates the expression of VEGF receptor 2 (VEGFR2) and is associated with its activation. Knockdown of VEGF in shear stressed HUVECs blocks the protective effect of shear stress, resulting in EC apoptosis equivalent to that in control ECs cultured under static conditions. Similarly, treatment of ECs subjected to arterial shear stress with the VEGF receptor tyrosine kinase inhibitor SU1498, or VEGFR2 neutralizing antiserum, led to increased apoptosis, demonstrating that the mechanoprotection from increased shear is mediated by VEGFR2. Taken together, these studies suggest that arterial flow induces VEGF-VEGFR2 autocrine-juxtacrine signaling, which is a previously unidentified mechanism for vascular EC survival in adult arterial blood vessels.

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“…13,14 In addition, Li and colleagues 15 showed that increased pressure flow could induce messenger RNA expression, which in turn induces the synthesis of adhesion molecules and cytokine in distal pulmonary artery endothelial cells. In a study concerning PAH caused by high blood flow in rats, Jin and associates 16 detected that serum and tissue ICAM-1 levels (associated with vascular inflammation) were significantly higher in rats with induced shunting than in the healthy control group.…”

Section: Discussionmentioning

confidence: 99%

Serum Levels of Soluble ICAM-1 in Children with Pulmonary Artery Hypertension

Oğuz¹,

Aydın²,

Sanli³

et al. 2014

Texas Heart Institute Journal

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This prospective cross-sectional study attempted to determine both the usefulness of the serum intercellular adhesion molecule-1 (ICAM-1) as a biomarker for pulmonary artery hypertension secondary to congenital heart disease and the nature of this marker's association with catheter angiographic findings.Our C ongenital heart disease (CHD) is the most common congenital malformation: the prevalence of moderate and severe forms of CHD is about 6 in 1,000 live births, or 19 in 1,000 live births if potentially serious cases of bicuspid aortic valve are included.1 Pulmonary artery hypertension (PAH) is a frequent complication of CHD, particularly in patients who have left-to-right shunts.2 Pulmonary artery hypertension has been defined as an increase in mean pulmonary artery pressure (PAP) of ≥25 mmHg at rest, as evaluated by right-sided heart catheterization. 3Pulmonary artery hypertension has a multifactorial pathogenesis that involves various biochemical pathways and cell types. The increase in pulmonary vascular resistance is related to different mechanisms, including vasoconstriction, proliferative and obstructive remodeling of the pulmonary vessel wall, inflammation, and thrombosis. Persistent exposure of the pulmonary vasculature to increased blood flow and pressure can result in endothelial dysfunction and endothelial damage.2 After such damage, endothelial cells produce an array of cytokines and growth factors and promote immune cells to adhere to and migrate through the vessel wall into the extravascular space. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are expressed on endothelial cells. When overexpressed on the activated endothelial layer, VCAM-1 and ICAM-1 undergo shedding, and their soluble forms (detectable in serum) are considered to be markers of endothelial cell activity or injury. 5,6 In the medical literature, 7-9 elevated serum concentrations of adhesion molecules have been detected in several diseases, such as diabetes mellitus, coronary heart disease, atherosclerosis, and rheumatoid arthritis. Sungprem and colleagues 10 showed that serum ICAM-1 level was increased in patients with PAH.

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High Pulsatility Flow Induces Adhesion Molecule and Cytokine mRNA Expression in Distal Pulmonary Artery Endothelial Cells.

Cited by 29 publications

References 0 publications

Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth

Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth

Role of shear-stress-induced VEGF expression in endothelial cell survival

Serum Levels of Soluble ICAM-1 in Children with Pulmonary Artery Hypertension

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