Novel mechanism by which extracellular matrix protein Nidogen-2 inhibits vascular calcification

On November 10, 2022, Professor Kong Wei of the Department of Physiology and Pathophysiology of Peking University School of Basic Medical Sciences, in collaboration with Professor Sun Jinpeng, published an online title in the internationally renowned cardiovascular journal Circulation Research The research paper "Nidogen-2 is a novel endogenous ligand of LGR4 to Inhibit Vascular Calcification" reveals the extracellular matrix protein Nidogen-2 as a result A novel endogenous biased ligand of LGR4 inhibits a novel mechanism
of vascular calcification.

Vascular calcification is recognized as an independent risk factor
for cardiovascular morbidity and mortality.
Although considerable progress has been made in elucidating the molecular mechanism regulation of vascular calcification, the complexity of its pathological process has hindered the development of potential treatments, and vascular calcification remains a tricky problem
.
Nestin 2 (Nidogen-2) is one of the important components of the basement membrane, and recent studies have found that it is essential for maintaining the contractile phenotype of vascular smooth muscle, but its role in vascular calcification has not been proven
.

The study found that Nidogen-2 expression was significantly downregulated during calcification through three mouse aortic calcification models and in vitro hyperphosphorus-induced calcification models of vascular smooth muscle cells.

The level of aortic calcification in Nidogen-2-deficient mice was significantly aggravated, suggesting that Nidogen-2 had a protective effect
on inhibiting the occurrence and development of vascular calcification.
Protein interactomics analysis and in vivo validation experiments screened for the potential binding protein LGR4
of Nidogen-2.
LGR4 is a G protein-coupled receptor that is considered a key regulator of osteoblast and osteoclast differentiation
.
The exchange between Nidogen-2 and LGR4 was confirmed by co-immunoprecipitation, flow cytometry binding experiments, and surface plasmon resonance binding experiments of affinity combined
.
Interestingly, Nidogen-2 does not affect known Wnt and Gs signals downstream of LGR4, but rather selectively activates Gαq-PKCα-AMPKα1 signal, indicating that Nidogen-2 is a novel endogenous biased ligand of LGR4
.
In vivo and in vitro experiments further confirmed that Nidogen-2, as an endogenous protective factor in vascular smooth muscle cells in response to the action of various calcification factors, inhibits vascular calcification through the LGR4-Gαq-PKCα-AMPKα1 pathway
。 This study not only broadens our understanding of how the extracellular matrix subtly regulates vascular calcification, but also sheds light on an underappreciated but critical mechanism, namely endogenous, selective agonist pairs under physiological conditions Biased regulation
of G protein-coupled receptors.

Dr.
Yufei Chen and Dr.
Chenfeng Mao of Peking University School of Basic Medicine are co-first authors
of this paper.
Professor Kong Wei, Professor Sun Jinpeng and Dr.
Mao Chenfeng of Peking University School of Basic Medical Sciences are co-corresponding authors
of this paper.
The work was also supported
by Professor Luo Jian, Professor Zhang Weizhen and others.
The research was supported
by the National Natural Science Foundation of China Innovation Group, the National Natural Science Foundation of China Key Project and the National Key Research and Development Program.

Original link: style="margin-top:0pt; margin-bottom:0pt; text-indent:24pt; text-align:right; line-height:150%; widows:0; orphans:0; font-size:12pt">(School of Basic Medicine, Peking University)