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
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