From basic scientific research to the development of new drugs for pulmonary arterial hypertension: insights from activin-targeting agents

Figures

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  FIGURE 1. The three driving forces of pulmonary vascular remodelling associated with pulmonary arterial hypertension. The pulmonary vascular smooth muscle was immunolabelled in green using an anti-alpha smooth muscle actin antibody, the endothelium was labelled in red with a CD31 antibody, and the nuclei were stained in blue using DAPI (4′,6-diamidino-2-phenylindole). Scale bar: 50 µm.

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  FIGURE 2. The activin signalling pathway. The activin signalling pathway is a subset of the bone morphogenetic protein (BMP)/transforming growth factor (TGF)-β pathway. Activins are dimers composed of two inhibin-beta chains (inhibin-βA and -βB) that have a high affinity for the type 2 receptors, ACTRIIA and ACTRIIB. Upon binding of activin A, activin B or activin A/B, these receptors recruit a type 1 receptor (ALK4 or ALK7). This recruitment leads to the phosphorylation of Smad2/3, which occurs to varying degrees and durations. The phosphorylated Smad2/3 then translocates to the nucleus in complex with Smad4 to regulate the expression of target genes involved in various cellular functions. These cellular functions include the modulation of endothelial cell activities such as tube formation, the regulation of smooth muscle cell contractility, and the recruitment and activation of inflammatory and immune cells. The pathway is tightly regulated at multiple levels, starting from the formation of activin dimers. The inhibin-β chains can also bind to an inhibin-α chain to form inhibin A and inhibin B, which do not induce the phosphorylation of Smad2/3. Furthermore, the binding of activin A, B,…

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  FIGURE 3. Integration of human and preclinical research to advance pulmonary arterial hypertension (PAH) understanding and treatment. This schematic illustrates how merging human data (e.g. clinical samples, imaging) with preclinical research (e.g. animal models, cell cultures, bioengineered systems) can deepen our understanding of PAH pathophysiology. It highlights the synergy between these approaches in validating research hypotheses and developing innovative treatments. CM: cardiomyocyte; CO: cardiac output; EC: endothelial cell; ECM: extracellular matrix; Echo: echocardiography; iPSC: induced pluripotent stem cell; mPAP: mean pulmonary artery pressure; PCLS: precision-cut lung slices; PH: pulmonary hypertension; SMC: smooth muscle cell.

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  FIGURE 4. The three most commonly used preclinical models of pulmonary hypertension for studying pulmonary vascular remodelling: chronic hypoxia (CHx) in mice and rats, and monocrotaline (MCT) and sugen/hypoxia (SuHx) in rats. The left side of the diagram illustrates commonly used experimental protocols to explore molecular mechanisms and evaluate the efficacy of potential drugs in both preventive and curative approaches. On the right side of the diagram, specific examples are provided, including pulmonary haemodynamic measurements obtained through right heart catheterisation, assessments of right ventricle (RV) remodelling using the Fulton index and two-dimensional echocardiography visualisation of the four cardiac chambers, and images showing small pulmonary artery (PA) muscularisation with immunostaining for α-smooth muscle actin (stained in brown). These data were obtained in Sprague Dawley rats weighing 100 g at the start of each protocol. mPAP: mean pulmonary artery pressure; LV: left ventricle.