In a groundbreaking study published in Nature Communications, researchers have unveiled critical new insights into the molecular interactions governing vascular endothelial cell function, casting new light on the intricate signaling mechanisms that regulate blood vessel development and maintenance. This study elucidates the pivotal role of endoglin, a well-known co-receptor, in modulating Bone Morphogenetic Protein 9 (BMP9) signaling through its effect on prodomain displacement and recruitment of the Transforming Growth Factor Beta Receptor II (TGFBRII) in vascular endothelial cells. The findings not only challenge existing paradigms about receptor complex formation but also open promising avenues for targeted therapeutic interventions in vascular diseases.
Blood vessel endothelial cells orchestrate complex signaling pathways to maintain vascular integrity, respond to mechanical cues, and regulate angiogenesis. Among these, the BMP9 signaling axis plays a quintessential role in vascular quiescence and homeostasis. Previously, BMP9 was understood to engage primarily with its high-affinity receptor ALK1 (Activin receptor-like kinase 1), an interaction modulated by auxiliary proteins like endoglin. However, the precise molecular choreography and how endoglin influences this signaling cascade had remained shrouded in mystery until now.
This new research dives deeply into the structural and functional interplay between endoglin and BMP9. Utilizing cutting-edge biochemical and biophysical techniques combined with live cell imaging, the authors reveal that endoglin serves as a BMP9 co-receptor by orchestrating the displacement of the BMP9 prodomain — a regulatory segment that keeps BMP9 in an inactive conformation — thereby facilitating ligand activation and receptor complex assembly. This displacement appears to be a prerequisite for the subsequent recruitment of TGFBRII, a serine/threonine kinase receptor traditionally associated with TGF-β signaling but now found to play an essential role in BMP9-mediated endothelial responses.
The prodomain displacement is a phenomenon that had intrigued scientists since the discovery that many TGF-β family ligands are secreted in latent, prodomain-bound forms. The present study highlights that endoglin’s interaction with BMP9 effectively pries apart this prodomain segment, converting BMP9 from an inactive to an active signaling state. This mechanism ensures that BMP9 signaling is tightly regulated, preventing inappropriate activation that could lead to vascular pathologies.
TGFBRII recruitment emerges as another fascinating aspect of this signaling model. While BMP receptors classically signal through type I and type II receptors like ALK1 and BMPRII (BMP receptor type II), the discovery that TGFBRII is co-opted into this complex hints at an additional layer of cross-talk between the BMP and TGF-β pathways. By recruiting TGFBRII, endoglin-BMP9 complexes might propagate distinct downstream signals or modulate the intensity and duration of canonical BMP-induced SMAD phosphorylation events. Such nuanced control mechanisms are vital for the dynamic regulation of vascular remodeling, especially during developmental angiogenesis or response to injury.
To unravel these molecular events, the authors employed co-immunoprecipitation assays, surface plasmon resonance, and mutational analyses to map the binding interfaces and define the role of endoglin domains in prodomain displacement and receptor recruitment. The data unequivocally demonstrated that mutating particular residues in endoglin’s extracellular domain abrogated prodomain displacement and markedly attenuated BMP9’s ability to recruit TGFBRII—confirming the specificity and necessity of endoglin’s co-receptor function.
These findings reconceptualize endoglin not just as a passive scaffold but as an active enzymatic mimic or molecular chaperone that modulates ligand bioavailability and receptor assembly. This reframing has profound implications for understanding hereditary hemorrhagic telangiectasia (HHT), a vascular disorder caused by mutations in endoglin. Defective prodomain displacement or receptor recruitment mechanisms could underpin the pathogenesis of vascular malformations observed in HHT patients, suggesting new molecular targets for therapeutic intervention.
Moreover, the interplay between endoglin, BMP9, and TGFBRII holds promise for engineering novel interventions in diseases marked by aberrant angiogenesis, such as cancer, diabetic retinopathy, and atherosclerosis. By modulating endoglin function or mimicking prodomain displacement, it may be feasible to fine-tune BMP signaling to restore endothelial cell homeostasis or suppress pathological vessel growth.
The importance of this discovery extends beyond vascular biology. Since TGF-β superfamily ligands regulate a myriad of cellular processes, including immune responses and fibrosis, the prodomain displacement model mediated by endoglin raises intriguing questions about whether similar co-receptor mechanisms exist in other tissues or with other ligands. These insights could catalyze a new wave of research focused on prodomain dynamics as a universal regulatory mechanism in cytokine biology.
The study’s authors also employed sophisticated in vivo models to confirm the physiological relevance of their findings. Utilizing endoglin-deficient mice and BMP9 mutant variants unable to undergo prodomain displacement, the researchers observed impaired vascular development and altered endothelial signaling responses. These phenotypes mirrored human vascular diseases, thereby validating the translational potential of their mechanistic discoveries.
The structural basis of prodomain displacement was further explored using cryo-electron microscopy and molecular dynamics simulations, which unveiled how endoglin binding induces conformational rearrangements in BMP9. This displacement exposes receptor-binding epitopes on BMP9 previously masked by the prodomain, enabling the assembly of a receptor complex incorporating both ALK1 and TGFBRII. These atomic-level insights pave the way for rational drug design strategies aimed at modulating receptor-ligand interactions with unprecedented precision.
Intriguingly, the study also discusses how mechanical forces, such as shear stress exerted by blood flow, might influence the endoglin-BMP9-TGFBRII axis. Given endoglin’s established role as a mechanosensor, its ability to displace the prodomain and recruit receptors could be dynamically regulated in response to biomechanical cues, fine-tuning vascular responses in a spatiotemporal manner. This intersection of biochemical signaling with biomechanical regulation defines a sophisticated control system for vascular integrity.
What sets this study apart is the convergence of multidisciplinary approaches—spanning molecular biology, structural biophysics, computational modeling, and in vivo experimentation—all cohesively centered around a single but pivotal molecular interaction. The clarity and depth of mechanistic understanding achieved underscore the transformative potential of integrated research methodologies in decoding complex biological phenomena.
As the field moves forward, this research sets a new benchmark for studies on TGF-β superfamily signaling. Future investigations will likely explore whether pharmacological agents can selectively enhance or inhibit prodomain displacement, modulate endoglin expression, or interfere with TGFBRII recruitment as therapeutic strategies. Furthermore, examining this signaling axis in the context of other endothelial subtypes or pathological states promises to enrich our comprehension of vascular biology.
In sum, this landmark work not only expands the molecular landscape of BMP9 signaling by positioning endoglin at the heart of prodomain displacement and receptor recruitment but also reshapes our conceptual frameworks regarding receptor complex formation and functional versatility. It marks a significant leap toward deciphering the molecular grammar dictating vascular health and disease, illuminating new paths for interventions aimed at life-threatening vascular conditions.
Subject of Research:
Endoglin’s role as a co-receptor for BMP9 in vascular endothelial signaling, focusing on prodomain displacement and recruitment of TGFBRII.
Article Title:
Endoglin as a BMP9 co-receptor in vascular endothelial cells: prodomain displacement and TGFBRII recruitment.
Article References:
Guo, J., Kostrzyńska, K., Kamzolas, I. et al. Endoglin as a BMP9 co-receptor in vascular endothelial cells: prodomain displacement and TGFBRII recruitment. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67531-9
Image Credits: AI Generated
Tags: advancements in vascular researchblood vessel development mechanismsBMP9 signaling pathwayendoglin role in BMP9 signalingmolecular interactions in angiogenesisreceptor complex formation in vascular biologysignaling mechanisms in endothelial cellsstructural interplay of endoglin and BMP9TGFBRII recruitment in endothelial cellstherapeutic interventions for vascular diseasesvascular endothelial cell functionvascular integrity and homeostasis
