Disruptions of blood pressure (BP) circadian variation are closely associated with an increased risk of cardiovascular disease. Thus, gaining insights into the molecular mechanisms of BP circadian variation is essential for comprehending BP regulation. Human genetic analyses suggest that PR domain–containing protein 16 (PRDM16), a transcription factor highly expressed in vascular smooth muscle cells (VSMCs), is significantly associated with BP-related traits. However, the roles of PRDM16 in BP regulation are largely unknown. Here, we demonstrate that BP in VSMC-specific Prdm16 -KO ( Prdm16 ^SMKO ) mice was significantly lower than that in control mice during the active period, resulting in aberrant BP circadian variation. Mesenteric artery rings from Prdm16 ^SMKO mice showed a reduced response to phenylephrine. Mechanistically, we identified adrenergic receptor α 1d ( Adra1d ) as a transcriptional target of PRDM16. Notably, PRDM16 exhibited a remarkable circadian expression pattern and regulated the expression of clock genes, particularly Npas2 , which is crucial for BP circadian variation regulation. Consequently, PRDM16 deficiency in VSMCs caused disrupted BP circadian variation through a reduced response to adrenergic signaling and clock gene regulation. Our findings provide insights into the intricate molecular pathways that govern circadian fluctuations in BP.

Abdominal aortic aneurysm (AAA) is usually asymptomatic until life-threatening complications occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. The transcriptional regulator PR domain–containing protein 16 (PRDM16) is highly expressed in the aorta, but its functions in the aorta are largely unknown. By RNA-seq analysis, we found that vascular smooth muscle cell–specific (VSMC-specific) Prdm16 -knockout ( Prdm16 ^SMKO ) mice already showed extensive changes in the expression of genes associated with extracellular matrix (ECM) remodeling and inflammation in the abdominal aorta under normal housing conditions without any pathological stimuli. Human AAA lesions displayed lower PRDM16 expression. Periadventitial elastase application to the suprarenal region of the abdominal aorta aggravated AAA formation in Prdm16 ^SMKO mice. During AAA development, VSMCs undergo apoptosis because of both intrinsic and environmental changes, including inflammation and ECM remodeling. Prdm16 deficiency promoted inflammation and apoptosis in VSMCs. A disintegrin and metalloproteinase 12 (ADAM12) is a gelatinase that can degrade various ECMs. We found that ADAM12 is a target of transcriptional repression by PRDM16. Adam12 knockdown reversed VSMC apoptosis induced by Prdm16 deficiency. Our study demonstrated that PRDM16 deficiency in VSMCs promoted ADAM12 expression and aggravates AAA formation, which may provide potential targets for AAA treatment.

Thoracic aortic aneurysm (TAA) is a life-threatening vascular disease frequently associated with underlying genetic causes. An inadequate understanding of human TAA pathogenesis highlights the need for better disease models. Here, we established a functional human TAA model in an animal host by combining human induced pluripotent stem cells (hiPSCs), bioengineered vascular grafts (BVGs), and gene editing. We generated BVGs from isogenic control hiPSC-derived vascular smooth muscle cells (SMCs) and mutant SMCs gene-edited to carry a Loeys-Dietz syndrome (LDS)–associated pathogenic variant ( TGFBR1 ^A230T ). We also generated hiPSC-derived BVGs using cells from a patient with LDS ( Patient ^A230T/+ ) and using genetically corrected cells ( Patient ^+/+ ). Control and experimental BVGs were then implanted into the common carotid arteries of nude rats. The TGFBR1 ^A230T variant led to impaired mechanical properties of BVGs, resulting in lower burst pressure and suture retention strength. BVGs carrying the variant dilated over time in vivo, resembling human TAA formation. Spatial transcriptomics profiling revealed defective expression of extracellular matrix (ECM) formation genes in Patient ^A230T/+ BVGs compared with Patient ^+/+ BVGs. Histological analysis and protein assays validated quantitative and qualitative ECM defects in Patient ^A230T/+ BVGs and patient tissue, including decreased collagen hydroxylation. SMC organization was also impaired in Patient ^A230T/+ BVGs as confirmed by vascular contraction testing. Silencing of collagen-modifying enzymes with small interfering RNAs reduced collagen proline hydroxylation in SMC-derived tissue constructs. These studies demonstrated the utility of BVGs to model human TAA formation in an animal host and highlighted the role of reduced collagen modifying enzyme activity in human TAA formation.

Perivascular adipose tissue (PVAT) is increasingly recognized as an active vascular regulator that influences inflammation, metabolism, and atherosclerotic progression. In healthy vessels, PVAT displays brown adipose-like features and contributes to vascular protection, whereas PVAT dysfunction is associated with adipose whitening, inflammatory activation, and enhanced plaque formation. Circadian clock genes are major regulators of tissue metabolism, yet their role in PVAT biology and atherosclerosis remains incompletely understood. Here, we investigated the function of the core circadian factor BMAL1 in brown adipocytes and PVAT using a brown adipocyte-specific BMAL1 knockout model (Bmal1^BAKO) and ApoE-deficient atherosclerosis-prone mice. Transcriptomic profiling of thoracic aortic PVAT and abdominal aortic PVAT revealed that BMAL1 deficiency induces a shift in metabolic gene expression profiles characterized by upregulation of glycolytic and lipogenic gene programs, together with suppression of genes linked to thermogenic and vascular homeostasis. Mechanistically, BMAL1 loss increased Mlxipl (encoding ChREBP) expression, and ChREBP knockdown attenuated the glycolytic–lipogenic transcriptional response to BMAL1 depletion in cultured brown adipocytes. In parallel, BMAL1-deficient PVAT exhibited enlarged lipid droplets, increased oxidative stress-related transcriptional profile, and inflammatory remodeling accompanied by macrophage accumulation. In ApoE^−/− mice, brown adipocyte-specific BMAL1 deletion aggravated atherosclerotic lesion formation in both chow-fed aging mice and Western diet-fed young mice, without major changes in systemic energy balance. In conclusion, brown adipocyte BMAL1 deficiency was associated with ChREBP-linked metabolic reprogramming, loss of brown-like PVAT features, oxidative and macrophage-associated remodeling, and increased atherosclerosis.

Abdominal aortic aneurysm (AAA) lacks effective pharmacological therapies. Here, we investigate transcription factor 7–like 2 (TCF7L2), a genetic locus associated with both thoracic and abdominal aortic aneurysms, to elucidate its role in AAA pathogenesis. Integrating summary data–based Mendelian randomization (SMR) with single-cell RNA sequencing of human and mouse aortae, we identify TCF7L2 as a gene enriched in vascular smooth muscle cells (VSMCs) and causally linked to AAA development. Smooth muscle cell–specific TCF7L2 knockout significantly attenuates AAA formation across 3 distinct murine models (AAA induced by angiotensin II infusion, by β-aminopropionitrile/angiotensin II coadministration, and by elastase), independent of systemic blood pressure or lipid levels. Mechanistic studies reveal that TCF7L2 directly upregulates MMP14 and downregulates TIMP3 expression in vitro and in vivo, driving MMP2-mediated extracellular matrix (ECM) degradation. Concurrently, TCF7L2 represses integrin β ₁ (ITGB1) expression, reducing VSMC adhesion to the ECM. Collectively, these findings identify TCF7L2 as a key driver of pathological vascular remodeling in AAA, suggesting that targeting TCF7L2 may offer a novel therapeutic strategy for limiting AAA progression.