Neuropilin‐1 maintains dimethylarginine dimethylaminohydrolase 1 expression in endothelial cells, and contributes to protection from angiotensin II–induced hypertension

Abstract

Dimethylarginine dimethylaminohydrolases (DDAHs) are known to degrade asymmetric dimethylarginine, an endogenous inhibitor of NOS, and maintain vascular homeostasis; however, the regulatory pathways of DDAHs remain unclear. In this study, we aimed to define the role of transmembrane glycoprotein neuropilin-1 (NRP1) in the expression of DDAHs and investigate the potential roles of NRP1 in regulation of blood pressure. Short hairpin RNA-mediated knockdown of NRP1 reduced the level and mRNA stability of DDAH1 but not DDAH2 in HUVECs, whereas overexpression of NRP1 increased the mRNA stability of DDAH1. Meanwhile, mesenteric arteries and lung vascular endothelial cells of tamoxifen-inducible endothelial cell-specific NRP1 knockout mice exhibited decreased expression of DDAH1 and slightly increased expression of DDAH2. Mechanistically, the regulation of NRP1 on DDAH1 expression is mediated by a posttranscriptional mechanism involving miR-219-5p in HUVECs. Although the endothelial cell-specific NRP1 knockout mice did not exhibit any significant change in blood pressure at the basal level, they were more sensitive to low-dose angiotensin II infusion-induced increases in blood pressure. Our results show that NRP1 is required for full expression of DDAH1 in endothelial cells and that NRP1 contributes to protection from low-dose angiotensin II-induced increases in blood pressure.-Wang, Y., Wang, E., Zhang, Y., Madamsetty, V. S., Ji, B., Radisky, D. C., Grande, J. P., Misra, S., Mukhopadhyay, D. Neuropilin-1 maintains dimethylarginine dimethylaminohydrolase 1 expression in endothelial cells, and contributes to protection from angiotensin II-induced hypertension.

Inhibition of Dimethylarginine Dimethylaminohydrolase (DDAH) Enzymes as an Emerging Therapeutic Strategy to Target Angiogenesis and Vasculogenic Mimicry in Cancer

“…In alignment with this, downregulation of DDAH1 is reported in gastric cancer tissue and cell lines (193). In HUVECs, transmembrane glycoprotein neuropilin-1 increases DDAH1 expression, mediated by a post-transcriptional mechanism involving miR-219-5p (220). Although this regulation has not been assessed in cancer, miR-219-5p has been reported to have a tumor suppressive role in colon cancer (221,222) and ovarian cancer (223), which may in part relate to regulation of DDAH1.…”

Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19

“…SARS-CoV-2 does appear more infectious perhaps secondary to its use of three additional viral co-factors: neuropilin-1 (NRP-1), HDL scavenger receptor B1 (SR-B1), and CD147 [ 111 – 113 ]. Interestingly, AT2 has been linked to upregulation of these co-receptors [ 114 – 118 ]. If these findings are confirmed in COVID-19, it would suggest a pathologic feed-forward cycle in which the SARS-CoV-2-mediated decrease in ACE2 leads to a downstream proliferation of viral co-receptors.…”

Circular RNA circGSE1 promotes angiogenesis in ageing mice by targeting the miR-323-5p/NRP1 axis

“…NRP1 is a transmembrane glycoprotein that is expressed on blood vessels, neurons, immune cells, and many other types of mammalian cells and binds a range of structurally and functionally diverse extracellular ligands to regulate organ development and function [ 17 , 18 ]. NRP1 plays a pivotal role in EC angiogenesis [ 19 ], and the VEGFR2/NRP1 complex increases the binding affinity of VEGF165 by 10- to 20-fold.…”