# Sclerostin in Vascular Calcification: Hypoxia-Driven Regulation and Therapeutic Modulation by Natural Products

## TL;DR

This review explores how hypoxia and HIF-1α regulate sclerostin, a protein involved in vascular calcification, and how natural products may offer therapeutic potential.

## Contribution

The paper integrates novel mechanistic and translational insights on hypoxia-driven sclerostin regulation and its modulation by natural compounds.

## Key findings

- HIF-1α connects hypoxia to osteogenic pathways that influence vascular smooth muscle cell behavior.
- Sclerostin's role in vascular calcification is context-dependent, acting as both inhibitor and promoter.
- Natural products like polyphenols and flavonoids may modulate sclerostin through multiple pathways.

## Abstract

Vascular calcification (VC) is increasingly recognized as an actively regulated pathological process rather than passive mineral deposition, strongly associated with aging, atherosclerosis, and chronic kidney disease. Sclerostin, a Wnt signalling antagonist primarily expressed in osteocytes, has recently been implicated in VC, although its precise vascular role remains debated. This review aims to integrate mechanistic and translational evidence on how hypoxia and hypoxia-inducible factor-1α (HIF-1α) regulate sclerostin and contribute to vascular mineralisation.

Experimental studies demonstrate that HIF-1α activation links hypoxia to key osteogenic pathways, including BMP2, RUNX2, and Wnt/β-catenin signalling, thereby influencing phenotypic switching of vascular smooth muscle cells (VSMCs). Hypoxia exerts both stimulatory and suppressive effects on sclerostin depending on local tissue conditions, reflecting a context-dependent regulatory network. Preclinical and clinical data show that sclerostin can act as either a compensatory inhibitor or a pro-calcific mediator, depending on disease stage and metabolic environment. Emerging evidence further highlights natural products such as polyphenols, flavonoids, and marine-derived compounds that modulate sclerostin expression through oxidative, inflammatory, and Wnt-related pathways.

Sclerostin sits at a critical intersection between bone and vascular systems, where hypoxia-driven HIF signalling orchestrates its dual effects on mineral metabolism. Understanding the HIF–sclerostin axis provides new insight into the bone–vascular continuum and identifies potential therapeutic targets. Natural bioactive compounds capable of restoring sclerostin–Wnt balance may represent safe, multi-targeted strategies to mitigate VC progression, warranting further mechanistic and translational evaluation.