Cerebral cavernous (or capillary-venous) malformations (CCM) have a prevalence of about 0.1-0.5% in the general population. Genes mutated in CCM encode proteins that modulate junction formation between vascular endothelial cells. Mutations lead to the development of abnormal vascular structures. In this article, we review the clinical features, molecular and genetic basis of the disease, and management.

Background-New vessel formation contributes to organ development during embryogenesis and tissue repair in response to mechanical damage, inflammation, and ischemia in adult organisms. Early angiogenesis includes formation of an excessive primitive network that needs to be reorganized into a secondary vascular network with higher hierarchical structure. Vascular pruning, the removal of aberrant neovessels by apoptosis, is a vital step in this process. Although multiple molecular pathways for early angiogenesis have been identified, little is known about the genetic regulators of secondary network development. Methods and Results-Using a transcriptomics approach, we identified a new endothelial specific gene named FYVE, RhoGEF, and PH domain-containing 5 (FGD5) that plays a crucial role in vascular pruning. Loss-and gain-of-function studies demonstrate that FGD5 inhibits neovascularization, indicated by in vitro tube-formation, aortic-ring, and coated-bead assays and by in vivo coated-bead plug assays and studies in the murine retina model. FGD5 promotes apoptosis-induced vaso-obliteration via induction of the hey1-p53 pathway by direct binding and activation of cdc42. Indeed, FGD5 correlates with apoptosis in endothelial cells during vascular remodeling and was linked to rising p21 Key Words: angiogenesis-inducing agents Ⅲ apoptosis Ⅲ endothelium Ⅲ FGD5 Ⅲ models, animal V ascularization during development and regeneration plays a vital role in adult disease progression, including tumor growth and metastasis, arthritis, diabetic retinopathy, and cardiovascular disease. Vascular growth in both development and disease consists of a strictly orchestrated, multistep process that requires integrated activation of several molecular pathways. During early vascular growth, a dense primary vascular network without functional arterial and venous distinction is formed in response to low-oxygen conditions. This primitive system, consisting of small capillaries, is relatively unstable, with tip and stalk cell vessel structures expanding and collapsing at a high rate. Transition of this primary network into a stable secondary vasculature with a defined arterial/venous hierarchy of larger vessels that branch into a restricted capillary field requires intensive vascular remodeling, a late angiogenic process that includes neovessel stabilization and pruning of redundant vessel structures. 1,2 Editorial see p 3063 Clinical Perspective on p 3158The molecular regulation by angiogenic factors such as vascular endothelial growth factor (VEGF)-A and fibroblast growth factor that promote growth of the primary vasculature has been studied extensively. In contrast, the key molecular pathways that regulate the reorganization of this early network into the more mature secondary vascular structure are still largely undefined. For the process of vascular pruning, vaso-obliteration by apoptosis induced by hyperoxia has been described, 3 but little is known about the molecular regulation of this important aspect in vascular remodeling that dete...

Primary human aorta-derived VSMC (Lonza, Breda, NL) were cultured on gelatin-coated plates at 37°C/5% CO 2 in SmGM-2 medium Objective-In cardiovascular regulation, heme oxygenase-1 (HO-1) activity has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation by promoting cell cycle arrest at the G1/S phase. However, the effect of HO-1 on VSMC migration remains unclear. We aim to elucidate the mechanism by which HO-1 regulates PDGFBB-induced VSMC migration. Methods and Results-Transduction of HO-1 cDNA adenoviral vector severely impeded human VSMC migration in a scratch, transmembrane, and directional migration assay in response to PDGFBB stimulation. Similarly, HO-1 overexpression in the remodeling process during murine retinal vasculature development attenuated VSMC coverage over the major arterial branches as compared with sham vector-transduced eyes. HO-1 expression in VSMCs significantly upregulated VEGFA and VEGFR2 expression, which subsequently promoted the formation of inactive PDGFR/VEGFR2 complexes. This compromised PDGFR phosphorylation and impeded the downstream cascade of FAK-p38 signaling. siRNA-mediated silencing of VEGFA or VEGFR2 could reverse the inhibitory effect of HO-1 on VSMC migration. Conclusion-These findings identify a potent antimigratory function of HO-1 in VSMCs, a mechanism that involves VEGFA and VEGFR2 upregulation, followed by assembly of inactive VEGFR2/PDGFR complexes that attenuates effective PDGFR signaling. (Arterioscler Thromb Vasc Biol . 2012;32:1289-1298 .) PdGF-induced Migration of Vascular smooth

Rationale: Neovascularization is required for embryonic development and plays a central role in diseases in adults. In atherosclerosis, the role of neovascularization remains to be elucidated. In a genome-wide microarrayscreen of Flk1؉ angioblasts during murine embryogenesis, the v-ets erythroblastosis virus E26 oncogene homolog 2 (Ets2) transcription factor was identified as a potential angiogenic factor. Objectives:We assessed the role of Ets2 in endothelial cells during atherosclerotic lesion progression toward plaque instability. Methods and Results:In 91 patients treated for carotid artery disease, Ets2 levels showed modest correlations with capillary growth, thrombogenicity, and rising levels of tumor necrosis factor-␣ (TNF␣), monocyte chemoattractant protein 1, and interleukin-6 in the atherosclerotic lesions. Experiments in ApoE ؊/؊ mice, using a vulnerable plaque model, showed that Ets2 expression was increased under atherogenic conditions and was augmented specifically in the vulnerable versus stable lesions. In endothelial cell cultures, Ets2 expression and activation was responsive to the atherogenic cytokine TNF␣. In the murine vulnerable plaque model, overexpression of Ets2 promoted lesion growth with neovessel formation, hemorrhaging, and plaque destabilization. In contrast, Ets2 silencing, using a lentiviral shRNA construct, promoted lesion stabilization. In vitro studies showed that Ets2 was crucial for TNF␣-induced expression of monocyte chemoattractant protein 1, interleukin-6, and vascular cell adhesion molecule 1 in endothelial cells. In addition, Ets2 promoted tube formation and amplified TNF␣-induced loss of vascular endothelial integrity. Evaluation in a murine retina model further validated the role of Ets2 in regulating vessel inflammation and endothelial leakage. Key Words: angiogenesis Ⅲ atherosclerosis Ⅲ endothelium Ⅲ vascular inflammation Ⅲ vulnerable plaque A therosclerosis is a complex disease with a strong inflammatory component, [1][2][3][4] initially triggered by endothelial dysfunction and characterized by an influx of atherogenic lipoprotein components, combined with endothelial upregulation of proinflammatory cytokines and adhesion molecules. 5 Monocyte adhesion and extravasation perpetuate the disease by further differentiation into macrophages and foam cells, ultimately driving atherosclerotic lesion growth and complexity. 6 Vulnerable plaque (VP) is an advanced form of atherosclerosis, characterized by an exuberated inflammatory response with the formation of a large necrotic core, and a rupture-prone thin fibrous cap. 7 In these VPs, microvessel formation with extravasation of erythrocytes in the vasa vasorum and intimal area has been observed. 8 -10 Although new vessel formation in advanced atherosclerosis has been associated with lesion progression and instability, 10 -12 the exact molecular mechanisms that facilitate neovascularization in atherosclerosis must be further elucidated. Conclusions:Recently, we have conducted a genome-wide screen to identify new geneti...

Rationale: Neovascularization stimulated by local or recruited stem cells after ischemia is a key process that salvages damaged tissue and shows similarities with embryonic vascularization. Apelin receptor (Aplnr) and its endogenous ligand apelin play an important role in cardiovascular development. However, the role of apelin signaling in stem cell recruitment after ischemia is unknown.Objective: To investigate the role of apelin signaling in recruitment after ischemia. Methods and Results:

Iodothyronine deiodinases catalyze the conversion of the thyroid prohormone T(4) to T(3) by outer ring deiodination (ORD) of the iodothyronine molecule. The catalytic cycle of deiodinases is considered to be critically dependent on a reducing thiol cosubstrate that regenerates the selenoenzyme to its native state. The endogenous cosubstrate has still not been firmly identified; in studies in vitro the sulfhydryl reagent dithiothreitol (DTT) is commonly used to activate ORD. We now have characterized an ORD activity in the teleost gilthead seabream (Sparus auratus) that is inhibited by DTT. DTT inhibited reverse T(3) (rT(3)) ORD by 70 and 100% in kidney homogenates (IC(50) 0.4 mmol/liter) and microsomes (IC(50) 0.1 mmol/liter), respectively. The omission of DTT from the incubation medium restored renal ORD Michaelis-Menten kinetics with a Michaelis constant value of 5 mumol/liter rT(3) and unmasked the inhibition by 6-n-propyl-2-thiouracil. A putative seabream deiodinase type 1 (saD1), derived from kidney mRNA, showed high homology (> or = 41% amino acid identity) with vertebrate deiodinases type 1. Features of this putative saD1 include a selenocysteine encoded by an in-frame UGA codon, consensus sequences, and a predicted secondary structure for a selenocysteine insertion sequence and an amino acid composition of the catalytic center that is identical with reported consensus sequences for deiodinase type 1. Remarkably, three of six cysteines that are present in the deduced saD1 protein occur in the predicted amino terminal hydrophobic region. We suggest that the effects of DTT on rT(3) ORD can be explained by interactions with the cysteines unique to the putative saD1 protein.

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THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions.