Endothelial dysfunction, beyond bradykinin, drives Hereditary Angioedema pathogenesis and offers new therapeutic targets.

Hereditary Angioedema (HAE) is a rare genetic disorder marked by recurrent vascular leakage and tissue swelling. Traditionally, excessive bradykinin generation has been considered the primary driver. However, current treatments, often targeting bradykinin pathways, still leave many patients with insufficient disease control. This highlights a critical gap in understanding the full spectrum of HAE pathogenesis, particularly the role of endothelial cells in modulating vascular permeability, which this review addresses.

This comprehensive review synthesizes recent advances in endothelial biology relevant to Hereditary Angioedema (HAE). It systematically examines existing literature to highlight how endothelial cells, through structures like intercellular junctions, the endothelial glycocalyx, and dynamic endothelial activation states, cooperatively regulate vascular barrier integrity. The authors integrated findings from various studies, including those on newly identified HAE subtypes, to propose a revised conceptual model for HAE pathogenesis.

The review establishes that endothelial cells play a decisive role in determining the timing and location of vascular permeability in Hereditary Angioedema (HAE), extending beyond the traditional focus on bradykinin excess. It highlights that intercellular junctions, the endothelial glycocalyx, and dynamic endothelial activation states are crucial cooperative regulators of barrier integrity. Newly identified HAE subtypes, stemming from pathogenic variants directly affecting endothelial regulatory pathways, further underscore endothelial dysfunction as a key disease mechanism. This evidence supports a paradigm shift:

The review proposes a revised conceptual model for HAE pathogenesis that integrates both bradykinin-dependent and bradykinin-independent processes within an endothelial-centered framework. This expanded understanding suggests new avenues for therapeutic intervention and biomarker discovery, moving beyond solely targeting bradykinin.