Our research aims to explore the functional diversification of vascular networks. Through a multidisciplinary approach utilizing advanced genetic tools, imaging technologies and bioinformatics, we seek to uncover and characterize previously unrecognized roles of the vasculature in different physiological and disease contexts.
We have discovered an unexpected organ-specific mechanism of lymphatic morphogenesis, which we termed lymphvasculogenesis, and identified novel lymphatic vessel origins in certain tissues (see: Circ Res 2015; Cell Rep 2015). These findings challenged the longstanding view that the lymphatic vasculature originates solely from veins and revealed the presence of progenitor populations with potential therapeutic applications for restoring lymphatic function. Our ongoing research aims to further explore the diverse origins of lymphatic vessels in different organs and their unique molecular signatures, which may uncover previously unknown biological functions of the lymphatic vasculature in regulating various organ-specific physiological processes.
When vascular development goes awry, it can result in vascular anomalies such as vascular malformations and lymphedema. These disorders are often cause by genetic mutations that disrupt normal vessel growth mechanisms, manifesting in organ- and vessel type-specific manner. In collaboration with geneticists and clinicians, we have identified and functionally characterized gene mutations responsible for some of these anomalies. By developing advanced mouse models, we are investigating the underlying mechanisms of these diseases and exploring potential therapeutic strategies (see: Nat Commun 2018; Nat Commun 2020; JEM 2023)
Endothelial cells in adult tissues are largely quiescent, yet they must continually maintain essential vascular functions. For example, a key challenge for lymphatic capillaries is to remain highly permeable for efficient fluid uptake while also withstanding rapid changes in tissue volume, such as during swelling, without losing structural integrity. Using advanced imaging techniques, we found that the endothelial cells lining these vessels are highly dynamic, continuously extending broad protrusions that overlap with neighboring cells. This behavior gives rise to their characteristic oak leaf–like shape, which plays a crucial role in reinforcing the mechanical stability of the monolayer while maintaining flexibility and permeability (See: Nature 2025). The shape and the mechanism underlying its acquisition are strikingly similar to the lobular morphology of plant leaf puzzle cells, an adaptation that allows them to withstand mechanical stress induced by turgor pressure.
Future questions we seek to address are how lymphatic vessels adapt and respond to physiological and pathological stresses such as upon wounding, inflammation and oedema.
Lymphatic vessels are present in nearly all tissues, where they likely play largely underexplored roles in maintaining tissue homeostasis and function. Recently, we identified a novel subtype of lymphatic endothelial cells (iLECs) residing at lymphatic capillary terminals, characterized by the expression of genes linked to immunomodulatory functions. Notably, we found that the iLEC population selectively expands and drives disease pathology in a genetic mouse model of lymphatic malformation (LM), a condition characterized by uncontrolled oncogene-driven vessel growth (See: Nat Commun 2020, J Exp Med 2023).
Our ongoing research aims to further investigate the role of iLECs in human physiology and their potential involvement in immune-related conditions, including psoriasis, wound healing, cancer, and vascular malformations.
To gain groundbreaking insights into vascular biology, we strive to overcome observational limitations by developing and utilizing cutting-edge genetic and imaging research tools. For example, we have generated and employed genetic mouse strains for targeted gene manipulation in LECs and their subpopulations, as well as disease models of lymphatic and venous malformations. We have employed advanced genetic models developed by Rui Benedito (CNIC, Madrid) for high-fidelity conditional gene targeting and genetic mosaics. Combined with longitudinal two-photon (2P) intravital imaging, these tools have allowed us to visualize endothelial cell behavior, therapy responses, cell shape and actin dynamics in vivo with unprecedented resolution (see: Nature 2025, Nat Cardiovasc Res 2025).
In parallel with in vivo technologies, we characterise the molecular using single-cell transcriptomics (see: JEM 2023, Vasc Biol 2024, Nat Cardiovasc Res 2025), and employ innovative methods and tools that replicate the vascular microenvironment in vitro. These include assays designed to simulate isotropic stretch of capillary vessels (see: Nature 2025).