Pulmonary vascular fibrosis in pulmonary hypertension – The role of the extracellular matrix as a therapeutic target

https://doi.org/10.1016/j.pharmthera.2023.108438Get rights and content

Abstract

Pulmonary hypertension (PH) is a condition characterized by changes in extracellular matrix (ECM) deposition and vascular remodeling of distal pulmonary arteries. These changes result in increased vessel wall thickness and lumen occlusion, leading to a loss of elasticity and vessel stiffening. Clinically, the mechanobiology of the pulmonary vasculature is becoming increasingly recognized for its prognostic and diagnostic value in PH. Specifically, increased vascular fibrosis and stiffening resulting from ECM accumulation and crosslinking may be a promising target for the development of anti- or reverse-remodeling therapies.

Indeed, there is a huge potential in therapeutic interference with mechano-associated pathways in vascular fibrosis and stiffening. The most direct approach is aiming to restore extracellular matrix homeostasis, by interference with its production, deposition, modification and turnover. Besides structural cells, immune cells contribute to the level of ECM maturation and degradation by direct cell-cell contact or the release of mediators and proteases, thereby opening a huge avenue to target vascular fibrosis via immunomodulation approaches. Indirectly, intracellular pathways associated with altered mechanobiology, ECM production, and fibrosis, offer a third option for therapeutic intervention. In PH, a vicious cycle of persistent activation of mechanosensing pathways such as YAP/TAZ initiates and perpetuates vascular stiffening, and is linked to key pathways disturbed in PH, such as TGF-β/BMPR2/STAT.

Together, this complexity of the regulation of vascular fibrosis and stiffening in PH allows the exploration of numerous potential therapeutic interventions. This review discusses connections and turning points of several of these interventions in detail.

Section snippets

Pathophysiology of PH – From remodeling to stiffening

Pulmonary hypertension (PH) is defined as elevated mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest, measured by right heart catheterization. In its various forms, PH affects approximately 1% of the world's population, thus presenting a severe global burden (Humbert et al., 2023). According to its etiology PH is divided into five clinical groups. Pulmonary arterial hypertension (PAH; Group 1) is a disease of the pulmonary vasculature, where an increase in pulmonary vascular resistance

ECM remodeling in PH

Remodeling of the ECM is a key characteristic of PH, encompassing changes in both their quantity and quality. Increased vascular fibrosis is observed quantitatively in all three layers of the vessel wall, with the intima layer showing the highest level of collagen deposition, followed by the media and adventitia (see Fig. 1, and (Hoffmann et al., 2015, Hoffmann et al., 2014; Jandl et al., 2020a; Zeder et al., 2022)).

At a qualitative level, alterations in the ECM impact its various components,

Targeting vascular fibrosis in PH via ECM modulation

As discussed above, the biomechanical changes in the pulmonary vasculature observed in PH patients are directly linked to increased biosynthesis, maturation, crosslinking, and deposition of ECM proteins. This presents a range of potential therapeutic interventions. Some of these interventions have already undergone translational studies and, in the most promising cases, have even led to the initiation of clinical trials (see below).

Increased biosynthesis, maturation, crosslinking, and

Targeting vascular fibrosis in PH via modulating immune system

Growing evidence suggests a functional link between immune cells and ECM remodeling in pulmonary hypertension, achieved through direct cell-cell interaction, the secretion of inflammatory cytokines/chemokines, or ECM-degrading enzymes.

In PAH, immune cell distribution in the lungs shifts from predominantly granulocytes to lymphoid cells. T-cells (including CD4+, CD8+ and γδ T-cells), various dendritic cells, mast cells and macrophages accumulate in the lungs and vessels, thereby affecting

Targeting vascular fibrosis in PH via the BMPR2/TGF-β axis

So far, various intracellular pathways have been identified that contribute to increased vessel fibrosis in PH. Among these pathways, the TGF-β and BMPR2 signaling pathways appear to be central to this process. These pathways are involved in the regulation of various cellular processes, including proliferation, differentiation, but also ECM production and vessel stiffening.

BMPR2 is a receptor for the bone morphogenetic protein (BMP) family of proteins and mutations in BMPR2 are the most common

Concluding remarks/potential clinical relevance

The complex pathology of pulmonary hypertension involves a range of cellular and molecular mechanisms that contribute to disease progression. Changes in the extracellular matrix composition and distal vessel stiffening are early events in the development of PH, and recent research has highlighted the crucial role played by immune cells in modulating vascular fibrosis in this condition. However, the interaction between immune cells, structural cells, and the extracellular matrix is complex, and

Declaration of Competing Interest

The authors declare no conflict of interest.

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