# Hippo in smooth muscle - a therapeutic target in vascular diseases driven by aging and hypertension

## TL;DR

This review explores how the Hippo signaling pathway, specifically YAP and TAZ, influences vascular health and disease, offering potential new therapeutic strategies for conditions like aneurysms and atherosclerosis.

## Contribution

The paper highlights the underexplored therapeutic potential of Hippo-YAP/TAZ signaling in vascular diseases, emphasizing the need for cell-specific targeting.

## Key findings

- YAP and TAZ are essential for maintaining vascular smooth muscle contractility and preventing aneurysms.
- In endothelial cells, YAP/TAZ promote atherosclerosis under disturbed blood flow and high cholesterol.
- Precise modulation of Hippo signaling could offer benefits for vascular repair while avoiding adverse effects.

## Abstract

The Hippo signaling pathway is a key regulator of cellular growth and organ size, acting through the transcriptional coactivators YAP and TAZ. These proteins shuttle between the nucleus and cytoplasm in response to Hippo pathway activity, which, when active, leads to cytoplasmic sequestration and degradation of YAP/TAZ, preventing them from initiating gene transcription. Although initially studied in development and cancer, recent research has revealed crucial functions for YAP and TAZ in the adult vascular wall.

This review discusses emerging insights into the roles of Hippo signaling and its downstream effectors YAP and TAZ in adult vascular smooth muscle cells (SMCs) and endothelial cells (ECs), with an emphasis on their physiological and pathological relevance.

In SMCs, YAP and TAZ are vital for maintaining contractile identity by regulating expression of SMC contractile proteins. Inducible deletion of YAP/TAZ in adult SMCs results in impaired contractility, hypotension, and spontaneous arterial aneurysms. Despite these findings, the role of upstream Hippo signaling in SMCs remains poorly understood, and its therapeutic potential is underexplored. In ECs, YAP and TAZ respond to disturbed flow patterns by promoting a pro-atherogenic gene expression profile, contributing to increased atherosclerotic burden in hypercholesterolemic conditions.

Targeting Hippo-YAP/TAZ signaling in vascular cells represents a promising yet complex strategy for treating vascular diseases. The key challenge lies in achieving precise, cell-specific, and temporally controlled modulation that enhances beneficial effects, such as aneurysm protection and arterial repair, while minimizing off-target or adverse effects in non-vascular tissues.