What is it about?

Fibrillin-1 is an extracellular matrix protein which assembles into microfibrils ensuring tissue integrity and elasticity. Mutations in the fibrillin-1 gene cause Marfan syndrome, an autosomal dominant disorder associated with severe cardiovascular, skeletal and ocular defects. While it is established that fibrillin-1 mutations cause weakening of the arterial wall, leading to aortic aneurysms and dissections, the consequences of these mutations on the microvasculature have not been explored. Our study reveals that fibrillin-1 regulates angiogenesis, the process of new blood vessel formation. During postnatal mouse development, in the brain or retina, fibrillin-1 is present in the extracellular matrix and colocalizes with microfibril-associated glycoprotein-1, MAGP1 at the angiogenic front. At this site, endothelial cells differentiate into motile and invasive tip cells. In a mouse model of Marfan syndrome carrying a fibrillin-1 mutation, retinal angiogenesis is compromised, endothelial sprouting is decreased and tip cell identity is impaired. In vitro, fibrillin-1 or MAGP1 deficiency impacts VEGF/Notch and Smad signaling which regulate the acquisition of endothelial tip cell identity. Intraocular injection of a wild-type C-terminal fibrillin-1 fragment prevents the angiogenesis defect observed in the retina of the fibrillin-1 mutant mouse. Proteomic analyses reveal that, in endothelial cells, the fibrillin-1 fragment upregulates the expression of ADAMTS1, a tip cell metalloprotease involved in matrix remodeling and cell invasion. These new findings, identify a transient matrix, enriched in fibrillin-1, MAGP1 and ADAMTS1, at the angiogenic front. This matrix plays a critical role during retinal neovascularization, regulating Notch signaling and matrix remodeling for robust endothelial sprouting.

Featured Image

Why is it important?

Angiogenesis plays a fundamental role in embryogenesis and proper functioning of the female reproductive system. It is also an essential tissue repair process, which we aim to stimulate in the context of ischemic diseases or regenerative medicine. Conversely, angiogenesis can be pathological, promoting the progression of various diseases. It aggravates cancer by feeding tumours and promoting their spread, and complicates inflammatory diseases. It is also responsible for retinopathy, the leading cause of blindness. Our results highlight that fibrillin-1 is a dynamic signaling platform in the regulation of endothelial cell specification and matrix remodeling at the angiogenic front. Moreover, a C-terminal fragment of the protein displays pro-angiogenic properties. These findings contribute to our understanding of the regulation of angiogenesis and open up new avenues for controlling vascularization. It may also have significant implications for people with Marfan syndrome.


The current study reveals that fibrillin-1 is an important player in blood vessel formation by regulating the behavior of endothelial cells. Future studies will explore the link between fibrillin-1 and the pathways involved in the acquisition of the tip cell phenotype and their invasive properties. Identifying the sequence of events and the way endothelial cells 'use' this fibrillin-1-rich matrix could help us increasing the efficacy of the C-terminal fragment to facilitate the transition to therapeutic applications. The long-term goal is to promote the reconstruction of vascular networks using these fibrillin-1-derived products for the repair of damaged tissue and regenerative medicine.

Florian Alonso
BIOTIS - INSERM U1026 The Laboratory for the Bioengineering of Tissues

Read the Original

This page is a summary of: Fibrillin-1 regulates endothelial sprouting during angiogenesis, Proceedings of the National Academy of Sciences, May 2023, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2221742120.
You can read the full text:




The following have contributed to this page