Matrix rules: microfibrillar protein controls vascular development

Comment on Chen et al, page 4364

In this issue, Chen and colleagues describe how a component of the extracellular matrix, microfibril-associated glycoprotein-1 (MAGP-1), plays a critical role in the vascular development of zebrafish by regulating blood vessel wall integrity and function via control of integrin-mediated cell-matrix interactions.

Recent advances in biomedical research, including the completion of genome sequencing, emphasize the need for functional analyses of genes regulating essential physiologic and pathologic processes. The zebrafish offers numerous advantages as a genetic model for in-depth studies of various aspects of development, including the formation of the cardiovascular system. Chen and colleagues developed a morpholino anti-sense oligonucleotide (MO)–based functional screen in zebrafish to identify previously unrecognized regulators of cardiovascular development. Using this approach, the group previously reported that syndecan-2, a cell-surface heparan sulfate proteoglycan, is an essential player in the process of angiogenesis in zebrafish.¹ FIG1 

In this issue, Chen and colleagues present a comprehensive in vivo study demonstrating that MAGP-1, a component of fibrillin-rich microfibrils, plays an essential role in vascular morphogenesis in zebrafish. Microfibrils are important structural components of most connective tissues, including, but not limited to, blood vessels, lungs, and elastic ligaments (reviewed in Kielty et al² ). The importance of microfibrils is underscored by the consequences of mutations in fibrillin-1 linked to the heritable disorder Marfan syndrome. For the first time, direct in vivo evidence linking microfibrillar protein MAGP-1 to vascular development and function is presented. Both underexpression and overexpression of MAGP-1 cause defects in vasculature, emphasizing the need for tight regulation of this protein during development. Knockdown of MAGP-1 results in the formation of a dilated caudal vein as well as blood vessels in the brain and eyes and irregular lumens of axial vessels (see figure). Reduced caudal-vein branching in MAGP-1 morphants suggests a critical role for MAGP-1 in vascular patterning. In situ hybridization studies combined with results of expression of an MAGP-1–monomeric RFP fusion construct revealed that MAGP-1 is expressed in regions of elastic-fiber formation and localized in areas where vascular dilation was observed in MAGP-1 morphants.

Chen and colleagues have shown that MAGP-1 morphants are characterized by the fragmented elastic fibers around dilated vessels. Furthermore, histologic analysis revealed the detachment and overall loose association of cells with the extracellular matrix in MAGP-1 morphants, indicating that MAGP-1 is required for maintaining the proper architecture of the blood vessel wall. Next, a synergism between subthreshold doses of MAGP-1 MO and an integrin antagonist resulting in blood vessel dilation was observed. This approach has proved very efficient in the identification of the functional relationships in vivo (which is one of the most difficult tasks in experimental biology).³  Thus, it appears that in vivo interaction between integrins and MAGP-1 might be involved in the regulation of vascular development. Of interest, MAGP-1 does not have an “RGD” motif within its sequence, in contrast to its closest relative, MAGP-2, which was previously identified as an integrin ligand.⁴  Furthermore, functional in vivo interaction between MAGP-1 and fibrillin-1 (both proteins are components of microfibrils) during vascular development was established. Thus, the study by Chen et al not only identifies MAGP-1 as a new regulator of elastic-fiber architecture, vasculature development, and function, but it also determines the functional partners for MAGP-1. These findings open avenues for further research and new clinical applications in cardiovascular disease. ▪