Project description:Formation and maturation of a functional blood vascular system is required for the development and maintenance of all tissues in the body. During the process of blood vessel development, primordial endothelial cells are formed and become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues. Specification of arterial and venous endothelial cells occurs in conjunction with suppression of endothelial cell cycle progression, and endothelial cell hyperproliferation is associated with potentially lethal arterial-venous malformations. However, the mechanistic role that cell cycle state plays in arterial-venous specification is unknown. Herein, studying vascular development in Cdh5-CreERT2;R26FUCCI2aR reporter mice, we find that venous and arterial endothelial cells exhibit a propensity for different cell cycle states during development and in adulthood. That is, venous endothelial cells are predominantly FUCCI-Negative, while arterial endothelial cells are enriched for the FUCCI-Red reporter. Single cell RNA sequencing analysis of developing retinal endothelial cells reveals that venous endothelial cells are enriched for the FUCCI-Negative state and BMP signaling, while arterial endothelial cells are enriched for the FUCCI-Red state and TGF-b signaling. Further transcriptional analyses and live imaging of cultured endothelial cells expressing the FUCCI reporter show that reporter-negative corresponds to an early G1 state and reporter-red corresponds to late G1 state. We find the early G1 state is essential for BMP4-induced venous gene expression, whereas late G1 state is essential for TGF-b1-induced arterial gene expression. In a mouse model of endothelial cell hyperproliferation and disrupted arterial-venous specification, pharmacological inhibition of endothelial cell cycle prevents the vascular defects. Collectively, our results show that endothelial cell cycle control plays a key role in arterial-venous network formation, and distinct cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous specification.

Project description:BACKGROUND AND PURPOSE:The residual blood flow artifact is a critical confounder for MR black-blood thrombus imaging of cerebral venous sinus thrombosis. This study aimed to conduct a validation of a new MR black-blood thrombus imaging technique with enhanced blood signal suppression. MATERIALS AND METHODS:Twenty-six participants (13 volunteers and 13 patients) underwent conventional imaging methods followed by 2 randomized black-blood thrombus imaging scans, with a preoptimized delay alternating with nutation for tailored excitation (DANTE) preparation switched on and off, respectively. The signal intensity of residual blood, thrombus, brain parenchyma, normal lumen, and noise on black-blood thrombus images were measured. The thrombus volume, SNR of residual blood, and contrast-to-noise ratio for residual blood versus normal lumen, thrombus versus residual blood, and brain parenchyma versus normal lumen were compared between the 2 black-blood thrombus imaging techniques. Segmental diagnosis of venous sinus thrombosis was evaluated for each black-blood thrombus imaging technique using a combination of conventional imaging techniques as a reference. RESULTS:In the volunteer group, the SNR of residual blood (11.3 ± 2.9 versus 54.0 ± 23.4, P < .001) and residual blood-to-normal lumen contrast-to-noise ratio (7.5 ± 3.4 versus 49.2 ± 23.3, P < .001) were significantly reduced using the DANTE preparation. In the patient group, the SNR of residual blood (16.4 ± 8.0 versus 75.0 ± 35.1, P = .002) and residual blood-to-normal lumen contrast-to-noise ratio (12.4 ± 7.8 versus 68.8 ± 35.4, P = .002) were also significantly lower on DANTE-prepared black-blood thrombus imaging. The new black-blood thrombus imaging technique provided higher thrombus-to-residual blood contrast-to-noise ratio, significantly lower thrombus volume, and substantially improved diagnostic specificity and agreement with conventional imaging methods. CONCLUSIONS:DANTE-prepared black-blood thrombus imaging is a reliable MR imaging technique for diagnosing cerebral venous sinus thrombosis.

Dataset Information

Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus.

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Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus.

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