von Willebrand Factor: An Unhealthy Bond between Lung Endothelium and Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a severe lung disease characterized by progressive scarring of lung tissue, which ultimately results in significant lung function loss, poor quality of life, and premature mortality (1, 2). Despite considerable research, a curative therapy for IPF remains elusive. The defining feature of IPF is fibroblastic foci—lesions of proliferating mesenchymal cells—acting as sites of fibrogenesis. In addition, emerging evidence points to the pulmonary vasculature as a key player in fibrosis (1–3). Endothelial-to-mesenchymal transition (EndoMT) is recognized as a potential fibrogenesis driver, with endothelial cells adopting mesenchymal traits that increase myofibroblast populations (4). Pulmonary vascular dysfunction and fibrotic progression interact bidirectionally. Pulmonary fibrosis can cause endothelial dysfunction, vascular remodeling, and pulmonary hypertension, commonly seen in IPF, which worsens clinical outcomes and increases mortality (1–3, 5, 6). Endothelial dysfunction may exacerbate fibrogenesis by enhancing fibroblast activation, promoting matrix deposition, and perpetuating tissue remodeling (7). These observations support a self-reinforcing loop whereby pulmonary fibrosis and endothelial dysfunction enhance each other. This cycle underscores the need to clarify the cellular and molecular mechanisms governing interactions among pulmonary vascular and fibrogenic mesenchymal cells. Understanding these processes could reveal novel therapeutic targets and lead to more effective treatments for this progressive, incurable disease.

In this issue of the Journal, Wang and colleagues (pp. 906–919) report a causal link between von Willebrand factor (vWF) and the progression of pulmonary fibrosis (8) (Figure 1). vWF is essential in the intrinsic coagulation cascade, mediating factor VIII–dependent clotting. It is synthesized and stored in Weibel-Palade bodies of endothelial cells, released through a regulated secretory pathway (9, 10). Thrombocytes are another source of vWF (10). Although all lung endothelial cells express vWF in culture, the pulmonary microvascular capillary endothelium does not show vWF expression in vivo. The authors present evidence demonstrating elevated vWF expression in patients with IPF. Using both in vitro and in vivo models, they show that deficiency of vWF leads to attenuated fibrosis and uncover a mechanism for the suppression of EndoMT. In addition, vWF deficiency is associated with reduced pulmonary vascular remodeling and decreased recruitment of M2-polarized macrophages. These effects were partially attributed to the inhibition of the canonical wingless-type MMTV integration site family, member (WNT) signaling pathway.

Figure 1.

Human lung tissue from patients with IPF contained elevated von Willebrand factor (vWF) expression. In cultured human lung microvascular endothelial cells, gene silencing of vWF (siRNA) reduced bleomycin-induced expression of WNT1, WNT4, WNT9A, and actin α2, smooth muscle (ACTA2), as well as inhibited EndoMT. In a mouse model of pulmonary fibrosis induced by bleomycin instillation, vWF-knockout mice exhibited increased survival, reduced lung fibrosis, pulmonary EndoMT, lung vascular remodeling, and pulmonary macrophage accumulation. Furthermore, vWF-knockout mice had reduced β-catenin and Wnt ligand expression. Created using BioRender (https://biorender.com/izotpu1). EndoMT = endothelial-to-mesenchymal transition; IPF = idiopathic pulmonary fibrosis; WNT 1 = wingless-type MMTV integration site family, member 1.

Overall, Wang and colleagues (8) shine a spotlight on the endothelium by examining the impact of vWF deficiency in pulmonary fibrosis. Their study centers on the hypothesis that vWF, as a mediator of endothelial function (and dysfunction), plays a significant role in driving lung fibrosis and that removing vWF ameliorates fibrotic injury. On the basis of their findings, Wang and colleagues propose that vWF is a critical mediator of the fibrogenic process by promoting EndoMT. Their observations position vWF both as a biomarker of disease progression and as a promising therapeutic target to modulate fibrosis in patients with IPF.

To evaluate this concept, the authors used the well-established bleomycin mouse model of pulmonary fibrosis and complementary cell culture experiments. Wang and colleagues (8) provide a compelling proof of concept that targeting VWF can ameliorate lung fibrosis. This finding broadens our perspective of IPF pathogenesis by highlighting endothelial dysfunction as both a consequence and a driving force in fibrosis (11–13). This study aligns with emerging evidence for a pathogenic role of dysfunctional endothelial cells in pulmonary fibrosis (1, 3, 7, 14, 15). The findings lead us in innovative directions: designing therapies that target the endothelium, using vascular biomarkers to guide treatment, and exploring the vascular–fibrotic interface in greater detail. Although significant work remains to translate these insights and test for patient benefits, this study lays a cornerstone and underscores the idea that reestablishing endothelial cell homeostasis and function could be an effective approach to treating pulmonary fibrosis. Thus, the work here has potential to usher in a new era of antifibrotic therapy that delivers meaningful improvements to patients with this intractable disease.

Despite its potential impact, the study by Wang and colleagues (8) has limitations. The pathology of IPF may originate from lung alveolar injury, but it is unclear whether the alveolar capillary endothelium is the source of vWF. This is important as vWF expression is not detected in the lung capillary endothelium in vivo (9). The use of cultured pulmonary microvascular endothelial cells in this work may contribute to this limitation, as vWF expression occurs in cultured pulmonary microvascular endothelium in vitro but not in vivo in capillaries (9). A better understanding of the source (e.g., conduit vessel endothelium or even thrombocytes) and timing of potential vWF release in fibrotic tissue will be necessary to resolve this discrepancy. The study also does not close the loop among endothelial dysfunction, vWF, and pulmonary hypertension. While observing reduced pulmonary alveolar capillary reorganization and pulmonary vascular medial thickness, Wang and colleagues did not include measurements of pulmonary vascular physiology or analysis of right ventricular remodeling. Therefore, studies are needed to clarify the link between pulmonary fibrosis, endothelial vWF, and pulmonary hypertension, which predicts increased mortality in IPF patients. Despite the intriguing questions left unanswered, we commend Wang and colleagues for their novel and potentially impactful work that demonstrates the critical role of vWF as a driver of EndoMT and pulmonary fibrosis.