Genetic Engineering Study Reveals Molecular Mechanism Controlling Blood Vessel Growth and Repair

Researchers have used advanced genetic engineering techniques to show that mice with a mutation in the gene encoding for the protein neuropilin 1 (NRP1) displayed abnormal arterial branching in their internal organs and were unable to establish networks of new blood vessels for restoration of blood flow in response to damage caused by heart attack.

The NRP1 gene encodes one of two neuropilins, which contain specific protein domains that allow them to participate in several different types of signaling pathways that control cell migration. Neuropilins contain a large N-terminal extracellular domain, made up of complement-binding, coagulation factor V/VIII, and meprin domains. These proteins also contain a short membrane-spanning domain and a small cytoplasmic domain. Neuropilins bind many ligands and various types of co-receptors that affect cell survival, migration, and attraction. Some of the ligands and co-receptors bound by neuropilins are vascular endothelial growth factor (VEGF) and semaphorin family members.

Investigators at Yale University (New Haven, CT, USA) and their collaborators at University College London (United Kingdom) genetically engineered a line of mice to lack the part of the the NRP1 gene that encodes for the protein's cytoplasmic tail (Nrp1cyto). They reported in the April 29, 2013, issue of the journal Developmental Cell that the circulatory systems of these animals contained poorly constructed arterial branches, and that the mice were unable to efficiently repair induced blood vessel blockage through the formation of new arteries.

The defect causing impaired formation of new blood vessels was traced to the absence of a PDZ-dependent interaction between NRP1 and the VEGF receptor 2 (VEGFR2) complex and synectin. The PDZ domain is a common structural domain of 80-90 amino-acids found in signaling proteins. PDZ is an acronym combining the first letters of three proteins, postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1), which were first discovered to share the domain. The PDZ domain helps anchor transmembrane proteins to the cytoskeleton and hold together signaling complexes. Synectin is a cytoplasmic domain-binding protein that inhibits cell migration.

"We have identified an important new mechanism that regulates VEGFR2 transport in vascular cells," said senior author Dr. Michael Simons, professor of medicine and cell biology at Yale University. "This opens new therapeutic opportunities for developing drugs that would either stimulate or inhibit blood vessel formation — important goals in cardiovascular and anticancer therapies, respectively."

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University College London