Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium

The importance of morphogenetic proteins (BMPs) and their antagonists in vascular development is increasingly being recognized. BMP-4 is essential for angiogenesis and is antagonized by matrix Gla protein (MGP) and crossveinless 2 (CV2), both induced by the activin receptor like-kinase 1 (ALK1) when stimulated by BMP-9. In this study, however, we show that CV2 preferentially binds and inhibits BMP-9 thereby providing strong feedback inhibition for BMP-9/ALK1 signaling rather than for BMP-4/ALK2 signaling. CV2 disrupts complex formation involving ALK2, ALK1, BMP-4, and BMP-9 required for the induction of both BMP antagonists. It also limits VEGF expression, proliferation, and tube formation in ALK1-expressing endothelial cells. In vivo, CV2 deficiency translates into a dysregulation of vascular BMP signaling, resulting in an abnormal endothelium with increased endothelial cellularity and expression of lineage markers for mature endothelial cells. Thus, mutual regulation by BMP-9 and CV2 is essential in regulating the development of the vascular endothelium.     

Urinary electrolytes and hypertension in elderly Kazakhs

Background. Deficiency of potassium (K) intake is associated with hypertension, and high dietary K intake may have a preventive effect. The prevalence of hypertension and incidence of stroke are higher in Kazakhs than in other ethnic groups in the People's Republic of China (PRC). The Barkol area in the Xinjiang region in PRC is an area with a high population of Kazakhs. We carried out a study in this region that involved blood pressure monitoring and the examination of serum and urinary electrolytes in the Kazakh and Han populations of the area. Methods. Twenty-four-hour ambulatory blood pressure monitoring and urine collections were performed for each study subject. In each subject, urine was collected simultaneously for 24 h during the blood pressure monitoring. Serum and urinary electrolytes were measured. Results. The prevalence of hypertension was higher in the Kazakh population than in the Han (men, 53%; women, 43% in the Kazakhs; men, 40%; women, 30% in the Han; P < 0.001). Urinary excretion of potassium was lower in Kazakhs than in Han (Kazakh, 18.9 ± 8.7 mmol/day; Han, 36.5 ± 11.3 mmol/day; P < 0.001). Urinary excretion of sodium was lower in Kazakhs than in Han (Kazakhs, 181.4 ± 77.6 mmol/day; Han, 194.1 ± 75.9 mmol/day; P < 0.001). Mean 24-h blood pressure was higher in Kazaks than in Han, and this value correlated positively with the urinary sodium/potassium ratio (r = 0.39; P < 0.001). Conclusions. The prevalence of hypertension was higher in Kazakhs than in Han in the Barkol area in the Xinjiang region. Kazakhs had a low intake of potassium. The sodium/potassium ratio was higher in Kazakhs than in Han. A high Na/K ratio, together with low intake of potassium, may be a factor in Kazakh hypertension. Received: February 8, 2001 / Accepted: July 5, 2001     

Dedifferentiated fat cells convert to cardiomyocyte phenotype and repair infarcted cardiac tissue in rats

Adipose tissue-derived stem cells have been demonstrated to differentiate into cardiomyocytes and vascular endothelial cells. Here we investigate whether mature adipocyte-derived dedifferentiated fat (DFAT) cells can differentiate to cardiomyocytes in vitro and in vivo by establishing DFAT cell lines via ceiling culture of mature adipocytes. DFAT cells were obtained by dedifferentiation of mature adipocytes from GFP-transgenic rats. We evaluated the differentiating ability of DFAT cells into cardiomyocytes by detection of the cardiac phenotype markers in immunocytochemical and RT-PCR analyses in vitro. We also examined effects of the transplantation of DFAT cells into the infarcted heart of rats on cardiomyocytes regeneration and angiogenesis. DFAT cells expressed cardiac phenotype markers when cocultured with cardiomyocytes and also when grown in MethoCult medium in the absence of cardiomyocytes, indicating that DFAT cells have the potential to differentiate to cardiomyocyte lineage. In a rat acute myocardial infarction model, transplanted DFAT cells were efficiently accumulated in infarcted myocardium and expressed cardiac sarcomeric actin at 8 weeks after the cell transplantation. The transplantation of DFAT cells significantly (p < 0.05) increased capillary density in the infarcted area when compared with hearts from saline-injected control rats. We demonstrated that DFAT cells have the ability to differentiate to cardiomyocyte-like cells in vitro and in vivo. In addition, transplantation of DFAT cells led to neovascuralization in rats with myocardial infarction. We propose that DFAT cells represent a promising candidate cell source for cardiomyocyte regeneration in severe ischemic heart disease.     

Beyond the bone: Bone morphogenetic protein signaling in adipose tissue

The bone morphogenetic proteins (BMPs) belong to the same superfamily as related to transforming growth factor β (TGFβ), growth and differentiation factors (GDFs), and activins. They were initially described as inducers of bone formation but are now known to be involved in morphogenetic activities and cell differentiation throughout the body, including the development of adipose tissue and adipogenic differentiation. BMP4 and BMP7 are the most studied BMPs in adipose tissue, with major roles in white adipogenesis and brown adipogenesis, respectively, but other BMPs such as BMP2, BMP6, and BMP8b as well as some inhibitors and modulators have been shown to also affect adipogenesis. It has become ever more important to understand adipose regulation, including the BMP pathways, in light of the strong links between obesity and metabolic and cardiovascular disease. In this review, we summarize the available information on BMP signaling in adipose tissue using preferentially articles that have appeared in the last decade, which together demonstrate the importance of BMP signaling in adipose biology.     

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

Cerebral arteriovenous malformations (AVMs) are common vascular malformations, which may result in hemorrhagic strokes and neurological deficits. Bone morphogenetic protein (BMP) and Notch signaling are both involved in the development of cerebral AVMs, but the cross-talk between the two signaling pathways is poorly understood. Here, we show that deficiency of matrix Gla protein (MGP), a BMP inhibitor, causes induction of Notch ligands, dysregulation of endothelial differentiation, and the development of cerebral AVMs in MGP null (Mgp^−/−) mice. Increased BMP activity due to the lack of MGP induces expression of the activin receptor-like kinase 1, a BMP type I receptor, in cerebrovascular endothelium. Subsequent activation of activin receptor-like kinase 1 enhances expression of Notch ligands Jagged 1 and 2, which increases Notch activity and alters the expression of Ephrin B2 and Ephrin receptor B4, arterial and venous endothelial markers, respectively. Reducing the expression of Jagged 1 and 2 in the Mgp^−/− mice by crossing them with Jagged 1 or 2 deficient mice reduces Notch activity, normalizes endothelial differentiation, and prevents cerebral AVMs, but not pulmonary or renal AVMs. Our results suggest that Notch signaling mediates and can modulate changes in BMP signaling that lead to cerebral AVMs.Cerebral arteriovenous malformations (AVMs) are abnormal vascular networks that form direct connections between arteries and veins, thereby short circuiting the cerebral capillary system. Due to the elevated blood pressure in these abnormal connections, vessels may ultimately rupture and result in hemorrhagic strokes (1–3). The development of cerebral AVMs has been shown to involve bone morphogenetic protein (BMP) and Notch signaling, both essential pathways in vascular formation (4, 5). Mutations in the genes for activin-like kinase receptor 1 (ALK1), a BMP type I receptor, and Endoglin, a coreceptor of ALK1, cause hereditary hemorrhagic telangiectasia (HHT) characterized by the presence of AVMs in multiple organs including the brain (6–9). Enhanced endothelial Notch signaling, as mediated by constitutively active Notch4, also promotes the formation of brain AVMs, whereas normalization of Notch4 activity results in regression of arteriovenous (AV) shunts (10, 11).We have previously shown that BMP-4 and -7 induce expression of ALK1 in endothelial cells (ECs) (12, 13). In turn, activation of ALK1 by its ligand BMP-9 induces expression of matrix Gla protein (MGP), an inhibitor of BMP-2, -4 and -7 (12-15), which is highly expressed in brain, lungs, and kidneys (13, 16). MGP provides negative feedback inhibition for BMP-4 and -7 (13, 17), which limits the ALK1 induction. Gene deletion of MGP in mice results in excess ALK1 activation and severe AVMs in lungs and kidneys (13). However, it has not yet been shown whether AVMs also form in the brain of MGP null (Mgp^−/−) mice.Connections between BMP-9/ALK1 and Notch signaling have been reported. Larrivée et al. reported that BMP-9/ALK1 activation induces the expression of Notch ligands and targets in vascular ECs (18), suggesting that Notch signaling acts on the vasculature downstream of BMP-9/ALK1. Even so, it is not clear how ALK1 signaling affects Notch signaling and vice versa during the formation of AVMs.Here, we report that the formation of cerebral AVMs occurs in Mgp^−/− mice, but is prevented by decreasing the expression of the Notch ligands Jagged 1 and 2, which compensates for the excess ALK1 activation in these mice. The results suggest that maintaining the balance between BMP and Notch signaling is essential to avoid AVMs.     

Concise review: applying stem cell biology to vascular structures

The vasculature, an organ that penetrates every other organ, is ideally poised to be the site where pools of stem cells are placed, to be deployed and committed in response to feedback regulation, and to respond to demands for new vascular structures. These pools of multipotent cells are often under the regulation of various members of the transforming growth factor-β superfamily, including the bone morphogenetic proteins and their antagonists. Regulation of stem cell populations affects their recruitment, differentiation, spatial organization, and their coordination with host tissue. Loss and dysregulation of feedback control cause a variety of diseases that involve ectopic tissue formation, including atherosclerotic lesion formation and calcification, diabetic vasculopathies, and arteriovenous malformations.     

White coat hypertension in centenarians

BACKGROUND: To study white coat (WC) hypertension in centenarians, a cross-sectional surveillance was carried out on Uygurs, a long-lived population in China. METHODS: Twenty-four-hour ambulatory blood pressure (BP) monitoring (ABPM) was performed in 33 centenarians (age range, 100 to 113 years) and compared with 100 elderly subjects (age range, 65 to 70 years). All subjects were clinically healthy and capable of self-care. Subjects had no history, signs, or symptoms of cardiovascular disease and were receiving no medical treatments. Office BP, 24-h mean, daytime and night-time BP, pulse pressure, heart rate, standard deviation (SD), and coefficient of variation (CV) of the same variables were extracted from ABPM. The WC effect was defined as the difference between mean office and daytime BP. RESULTS: Centenarians demonstrated higher prevalence of WC hypertension, compared to elderly group (15% vs. 5%). The WC effect was also greater in centenarians than in elderly subjects, and was more marked for systolic BP than for diastolic BP and heart rate. The WC effect for systolic BP was positively correlated with both SD (r = 0.45, P < .01) and CV (r = 0.55, P < .01) for 24-h systolic BP in centenarians, but not in elderly subjects. CONCLUSIONS: Prevalence of WC hypertension was greater in centenarians than in elderly subjects. The WC effect and BP variation may be increased in centenarians. Previously observed higher BPs seen in very elderly individuals might be explained by the greater impact of WC hypertension.     

Matrix Gla protein deficiency causes arteriovenous malformations in mice

Arteriovenous malformations (AVMs) in organs, such as the lungs, intestine, and brain, are characteristic of hereditary hemorrhagic telangiectasia (HHT), a disease caused by mutations in activin-like kinase receptor 1 (ALK1), which is an essential receptor in angiogenesis, or endoglin. Matrix Gla protein (MGP) is an antagonist of BMPs that is highly expressed in lungs and kidneys and is regulated by ALK1. The objective of this study was to determine the role of MGP in the vasculature of the lungs and kidneys. We found that Mgp gene deletion in mice caused striking AVMs in lungs and kidneys, where overall small organ size contrasted with greatly increased vascularization. Mechanistically, MGP deficiency increased BMP activity in lungs. In cultured lung epithelial cells, BMP-4 induced VEGF expression through induction of ALK1, ALK2, and ALK5. The VEGF secretion induced by BMP-4 in Mgp^–/– epithelial cells stimulated proliferation of ECs. However, BMP-4 inhibited proliferation of lung epithelial cells, consistent with the increase in pulmonary vasculature at the expense of lung tissue in the Mgp-null mice. Similarly, BMP signaling and VEGF expression were increased in Mgp^–/– mouse kidneys. We therefore conclude that Mgp gene deletion is what we believe to be a previously unidentified cause of AVMs. Because lack of MGP also causes arterial calcification, our findings demonstrate that the same gene defect has drastically different effects on distinct vascular beds.