Abstract
Abstract
Ischemic stroke remains a leading cause of mortality and disability worldwide, yet current therapeutic strategies, such as thrombolysis and thrombectomy, are constrained by narrow treatment windows and incomplete microvascular repair. While angiogenesis is pivotal for long-term functional recovery, the epigenetic mechanisms governing post-stroke vascular remodeling remain poorly understood.
Here, we demonstrate that the long non-coding RNA (lncRNA) Malat1 acts as a critical endothelial regulator of angiogenesis and neurological restoration. Using an endothelium-specific Malat1 overexpression mouse model (EC-Malat1 Tg), we demonstrate endothelial Malat1 upregulation enhances angiogenesis, restores cerebral blood flow, and improves sensorimotor and cognitive function following ischemic stroke.
Mechanistically, fluorescence-activated cell sorting (FACS)-based RNA sequencing of brain endothelial cells identified novel downstream targets of Malat1, including Hapln2, Bcl6, Esr1, Sox17, Tfrc, Hsp90aa1, and Tek. Among these, Tek (Tie2) showed robust endothelial co-localization and direct interaction with Malat1. Notably, while Malat1 overexpression markedly increased Tek protein expression, adeno-associated virus (AAV)-mediated endothelial knockdown of Tek abrogated the pro-angiogenic and neurovascular reparative effects of Malat1.
Collectively, our data establishes the Malat1-Tek axis as a novel signaling pathway essential for driving post-ischemic cerebrovascular remodeling and long-term functional recovery. Targeting Malat1 represents a novel restorative therapeutic approach for ischemic stroke.