Endothelial dysfunction in pulmonary arterial hypertension: loss of cilia length regulation upon cytokine stimulation

Abstract

Pulmonary arterial hypertension (PAH) is a syndrome characterized by progressive lung vascular remodelling, endothelial cell (EC) dysfunction, and excessive inflammation. The primary cilium is a sensory antenna that integrates signalling and fine tunes EC responses to various stimuli. Yet, cilia function in the context of deregulated immunity in PAH remains obscure. We hypothesized that cilia function is impaired in ECs from patients with PAH due to their inflammatory status and tested whether cilia length changes in response to cytokines. Primary human pulmonary and mouse embryonic EC were exposed to pro- (TNFα, IL1β, and IFNγ) and/or anti-inflammatory (IL-10) cytokines and cilia length was quantified. Chronic treatment with all tested inflammatory cytokines led to a significant elongation of cilia in both control human and mouse EC (by ∼1 µm, P < 0.001). This structural response was PKA/PKC dependent. Intriguingly, withdrawal of the inflammatory stimulus did not reduce cilia length. IL-10, on the other hand, blocked and reversed the pro-inflammatory cytokine-induced cilia elongation in healthy ECs, but did not influence basal length. Conversely, primary cilia of ECs from PAH patients were significantly longer under basal conditions compared to controls (1.86 ± 0.02 vs. 2.43 ± 0.08 µm, P = 0.002). These cilia did not elongate further upon pro-inflammatory stimulation and anti-inflammatory treatment did not impact cilia length. The missing length modulation was specific to cytokine stimulation, as application of fluid shear stress led to increased cilia length in the PAH endothelium. We identified loss of cilia length regulation upon cytokine stimulation as part of the endothelial dysfunction in PAH.

Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension

“…Besides BMPR2 mutations, insults such as inflammation, chronic hypoxia, and shear stress have been found to be involved in the pathogenesis of PAH. We demonstrated that the pro‐inflammatory cytokines TNF‐α and IL‐1β, previously found to be implicated in PAH , trigger autophagy in PAECs. Hurst et al reported that TNF‐α reduces BMPR2 transcription in PAECs .…”

Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells

“…Increased human serum IL6 protein levels are found across the systemic and lung circulation of PAH patients with mild-to-severe disease and are correlated with clinical phenotypes and outcomes in PAH subgroups [ 34 , 35 ]. Additionally, we have shown that pro- and anti-inflammatory cytokine responses in MVECs of PAH patients are impaired [ 36 ]. In this study, however, we demonstrate that BMP9 or IL6 alone are not sufficient to induce full mesenchymal trans-differentiation, as previously suggested [ 37 – 39 ], wherefore we postulate that IL6 plays a mechanistic respectively modulating role.…”

Primary Ciliary Signaling in the Skin—Contribution to Wound Healing and Scarring

“…Endothelial cell responses to FSS through PC help maintain barrier function, blood vessel wall permeability, and vascular tone (Jones et al, 2012;Peng et al, 2019). PC are also involved in endothelial cell inflammatory signaling, as their loss promotes vascular inflammation (Dinsmore and Reiter, 2016), and their length is controlled by cytokine stimuli, as mentioned above (Dummer et al, 2018). Defects in endothelial PC cause disorders of blood fluid-induced responses and result in vascular dysfunctions, such as hypertension, aneurysm, and atherosclerosis (Pala et al, 2018).…”