Formyl peptide receptor activation induces vascular plasticity and remodeling in hypertension

PROJECT SUMMARY WENCESLAU, CAMILLA F. One of the major pathophysiological characteristics of hypertension is the presence of vascular remodeling. Accordingly, it has been shown that 100% hypertensive subjects present small artery remodeling.

However, there is a gap in the literature in understanding the exact trigger that leads to vascular remodeling, and this may limit our ability to adequately treat and prevent hypertension. Recent evidence implicates immune mechanisms in the pathophysiology of hypertension.

Formyl peptide receptor (FPR)-1 is a pattern recognition receptor which plays a crucial role in the function of the innate immune system.

In fact, one of the most powerful signaling pathways that induces actin polymerization and neutrophil movement is mediated by FPR-1. Recently, we observed that this receptor is expressed in arteries.

Therefore, we questioned why a receptor that is crucial for immune defense and cell motility in leukocytes, would be expressed and functional in arteries?

We observed that activation of FPR-1 in arteries is important for the temporal reorganization of actin, which rapidly induces actin polymerization. FPR-1 is a G-protein-coupled receptor that can bind N-formyl peptides produced by bacterial degradation. Interestingly, mitochondria carry hallmarks of their bacterial ancestry.

Consequently, both mitochondrial and bacterial-derived peptides have a formyl group at their N-terminus.

Therefore, N-formyl peptides (NFPs), regardless of origin, are recognized by FPR-1 as pathogens and thus play a role in the initiation of inflammation. Here, we observed for the first time that NFPs are present in the circulation of hypertensive animals and humans.

Therefore, it is plausible to suggest that synergistic action of leaky gut-derived bacteria NFPs and cell damage-derived mitochondria NFPs lead to FPR-1 activation.

Consequently, FPR-1 activation maybe the trigger to induce vascular remodeling, via actin polymerization, and subsequently, hypertension. This planned research is uniquely suited to the NHLBI Early Stage Investigator (ESI)-Research Project Grant (R01).

It is innovative and has a strong, translational and multi-disciplinary research team of collaborators that have the capabilities and expertise to make this project successful.

As an independent ESI, my short-term goal is to use state-of-art approaches, including culture-pressure myographs, genetic-engineering technologies, and arteries from humans and animals to explore a major driving force behind vascular-immune network dysfunction in hypertension.