Daily Cardiology Research Analysis

Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system that can cause strokes and seizures. Aggressive CCM growth follows an endothelial cell two-hit mechanism in which enhanced MEKK3-KLF2/4 signaling stimulates PI3K signaling, but how these pathways are linked has been undefined. Here, we use human CCM specimens, two mouse models of CCM disease, and primary human endothelial cells to examine the roles of the major endothelial growth factor receptors, VEGFR2 and TIE2. We find no evidence of augmented VEGFR2 signaling in CCM lesions, and neither genetic nor pharmacologic blockade of VEGFR2 reduced CCM formation in mouse models. Instead, we observe markedly increased phospho-TIE2 levels in human and mouse CCM lesions, MEKK3-KLF2/4-driven induction of TIE2 receptor expression, and almost complete rescue of CCM formation following genetic or pharmacologic TIE2 blockade in mouse models. Our studies identify TIE2 as the molecular link between the MEKK3-KLF2/4 and PI3K signaling pathways during CCM formation and suggest that targeting TIE2 may be an effective means to treat human CCM disease.

Multiple germline and somatic genomic factors are associated with risk of coronary artery disease, but there is no single measure of risk that integrates all information from a DNA sample. To address this gap, we develop an integrated genomic model that includes six germline and somatic genetic drivers for coronary artery disease, including polygenic risk score, genetically-proxied proteomic/metabolomic risk scores, and clonal hematopoiesis of indeterminate potential. We evaluated its predictive power in the UK Biobank (N = 391,536), and validate it using data from the TOPMed program (N = 34,177). The 10-year coronary artery disease risk based on the integrated genomic model profile ranges from 1.1% to 15.5% in the UK Biobank and from 3.8% to 33.0% in TOPMed, with a more pronounced gradient in males than females. The integrated genomic model captures the cumulative effect of multiple genetic drivers, identifying individuals at high risk for coronary artery disease despite lacking any single high-risk genetic factor, as well as individuals at low risk despite carrying known high-risk factors. In middle age, the integrated genomic model augments the performance of the Pooled Cohort Equations, a clinical risk calculator for coronary artery disease. While the integrated genomic model yields only modest incremental predictive value over polygenic risk score at the population level, it identifies approximately 13% of high-risk individuals not detected by polygenic risk score alone.

Ion channels are the second most common clinical drug target besides G protein-coupled receptors. Aneurysmal diseases pose a significant threat to human life. Novel drug targets for its treatment remain to be explored. We investigated the role of an ion channel, calcium homeostasis modulators 5 (CALHM5), on the development of aortic aneurysms. We characterized CALHM5 as a plasma membrane ion channel abundant in smooth muscle cells of both humans and mice, playing a pivotal role in regulating calcium homeostasis. Notably, CALHM5 deficiency suppressed the transcription of the L-type calcium channel (LTCC) pore-forming subunit by downregulating cAMP-response element binding proteins. This in turn diminished blood vessel contractility and decreased blood flow. Intriguingly, CALHM5 expression is downregulated in smooth muscle tissues of aortic aneurysm patients. Furthermore, CALHM5 deficiency was observed to ameliorate the development of abdominal aortic aneurysms in mice, partly by stimulating smooth muscle cell proliferation. CALHM5 emerges as an ion channel prominently expressed in arterial smooth muscles, serving as a physiological regulator of smooth muscle contraction and presenting itself as a promising therapeutic target for aortic aneurysms.