Clonal analysis reveals a common progenitor for endothelial, myeloid, and lymphoid precursors in umbilical cord blood.

RATIONALE: several studies demonstrate that hematopoietic tissues are a source of endothelial progenitor cells, which contribute to newly formed blood vessels during tissue repair in adults. However, it is not clear which cell type in these hematopoietic tissues gives rise to endothelial progenitor cells. OBJECTIVE: to identity the origin of endothelial progenitors within the hematopoietic hierarchy and to assess their in vivo revascularization potential. METHODS AND RESULTS: using a single-cell sorting approach and in vitro multilineage differentiation assays, here we show that individual CD34(+)CD45(+)CD133(+)CD38(+) cells from cord blood uniquely have the ability to differentiate into T- and B-lymphoid, myeloid, and endothelial cells. The latter were characterized by the expression of VE-cadherin, KDR, von Willebrand factor, endothelial nitric oxide synthase, the lack of CD45, CD133, and c-fms (colony stimulating factor-1 receptor). Unexpectedly when transplanted into hindlimb ischemic NOD-scid IL2Rγ(null) mice, freshly isolated CD34(+)CD45(+)CD133(+)CD38(+) cells maintained their hematopoietic identity and were rarely found to integrate into host blood vessels. Nevertheless, they significantly improved perfusion, most likely through a paracrine mechanism. On the other hand, CD34(+)CD45(+)CD133(+)CD38(+) cells differentiated in vitro into endothelial cells were able to form vessels in vivo in both Matrigel plug and hindlimb ischemia transplantation assays. CONCLUSIONS: these findings indicate that the CD34(+)CD45(+)CD133(+)CD38(+) cell fraction contains a common progenitor for the hematopoietic and vascular lineages and may represent a valuable cell source for therapeutic applications.

Investigation of local ACE activity and structural alterations during development of L-NAME-induced hypertension.

Tonic basal release of nitric oxide (NO) by vascular endothelial cells controls blood pressure (BP) in the basal state. In the present study, we showed how serum and local angiotensin converting enzyme (ACE) alters during development of hypertension in chronic nitric oxide synthase blockade, a non-renin-dependent model of hypertension. Four experiments were performed in which animals were given N(omega)-nitro-L-arginine methyl ester (L-NAME) (50 mg kg(-1)) for 2, 4, 8 and 12 weeks. The control group rats received tap water. The ACE activity in serum, aorta, heart, kidney and lung was analyzed by high performance liquid chromatography (HPLC) and the structural change in aorta was investigated by measurement of cross-sectional area (CSA). Significant elevation of systolic blood pressure developed in chronically NO-blocked rats compared to controls. These results indicated that ACE activity in aortae and heart was gradually increased during development of hypertension and was more pronounced at higher blood pressure. Furthermore, there was a positive correlation between aortic cross-sectional area and elevation of blood pressure. These observations highlight the importance of the local ACE particularly in organs regulating hypertension (aorta and heart) during development of L-NAME-induced hypertension.

Investigation of circulatory and tissue ACE activity during development of lead-induced hypertension.

Prolonged exposure to low levels of lead causes systemic hypertension. Several mechanisms have been proposed to explain lead-induced hypertension. Recently, the etiological role of the renin-angiotensin system (RAS) has been investigated in this context. This study assessed the alterations of circulatory and tissue angiotensin converting enzyme (ACE) activity during development of lead induced hypertension. Male rats were divided to two main groups: lead-treated animals which received lead acetate, 100 ppm, in drinking water for 2, 4, 6, and 8 weeks and a control group given distilled water. The ACE activity in serum and tissues was analyzed by HPLC. The blood pressure gradually increased in correlation with lead exposure with time. The study also revealed significant elevation of local and serum ACE activity in the early phase of lead treatment; however, chronic lead exposure suppressed ACE activity in serum and tissues. These results emphasize the etiological role of ACE activity in the early phase of lead-induced hypertension.

Study of correlation between elevation of blood pressure and tissue ACE activity during development of hypertension in 1K1C rats.

OBJECTIVES: This study sought to examine the alteration of local angiotensin converting enzyme (ACE) activity in the aortae, heart, kidney and lung as well as plasma during the development of hypertension in one-kidney, one-clip (1K1C) model, a non-renin-dependent model of renovascular hypertension. METHODS: Experiments were carried out 2, 4, 8 and 12 weeks after induction of hypertension in male Sprague-Dawley rats. ACE activity was analyzed by high-performance liquid chromatography (HPLC) and the structural changes in aortae were investigated by measurement of cross-sectional area (CSA). RESULTS: Our results show that ACE activity in aortae and heart was gradually increased with the development of hypertension and was more pronounced at higher blood pressure. In addition, there was a positive correlation between aortic CSA and elevation of blood pressure. CONCLUSIONS: Our findings emphasize the significant role of local ACE, particularly in organs regulating hypertension (aortae and heart) in 1K1C model, in which circulatory renin is known to be unelevated.

Study of antihypertensive mechanism of Tribulus terrestris in 2K1C hypertensive rats: role of tissue ACE activity.

Tribulus terrestris is a natural herb used for treating many diseases including hypertension. According to previous reports, aqueous extract of tribulus fruits may have some antihypertensive effect with an unknown mechanism. The present study investigated the antihypertensive mechanism of tribulus in 2K1C hypertensive rats by measurement of circulatory and local ACE activity in aorta, heart, kidney and lung. Four groups of rats were selected; control, sham, operated or hypertensive and tribulus treated hypertensive group. Hypertension was induced using silver clip on renal artery by surgery. Four weeks after surgery, a single daily dose of 10 mg/kg of lyophilized aqueous extract of tribulus fruit were given orally to 2K1C rats for four weeks. ACE activity was determined by high performance liquid chromatography (HPLC). Blood pressure was measured by the tail-cuff method. The systolic blood pressure (SBP) was significantly increased in 2K1C rats compared to control rats. The SBP of tribulus fed hypertensive rats was significantly decreased compared to hypertensive rats. The ACE activity in all tissues of 2K1C rats including: aorta, heart, kidney, lung as well as serum were significantly increased compared to normal rats. The ACE activity in all tissues of tribulus fed hypertensive rats was significantly lower than that of hypertensive rats, which was more pronounced in kidney. These results indicated that there is a negative correlation between consumption of tribulus and ACE activity in serum and different tissues in 2K1C rats.

Investigation of antihypertensive mechanism of garlic in 2K1C hypertensive rat.

This study sought to examine the antihypertensive mechanism of garlic in two-kidney-one-clip (2K1C) hypertensive rat. In this study, the effect of garlic on serum and tissue including: aorta, heart, kidney, lung as well as circulatory (serum) ACE activity in 2K1C rats were examined. Four groups of rats were selected: control "CTL", sham-operated "SHAM", hypertensive "H" and garlic-treated hypertensive "GT" group. Hypertension was induced by surgery. Four weeks post-clipping, single daily dose of 50mg of aqueous extract of garlic was given orally to "GT" rats for 4 weeks. Blood pressure was measured by tail-cuff method. ACE activity was determined using HPLC. The systolic blood pressure (SBP) was significantly increased in "H" compared to "CTL" group. In "GT" group, blood pressure was significantly decreased compared to "H" group. The ACE activity in all tissues of "H" group was significantly increased compared to controls which was significantly decreased in garlic-treated compared to non-treated hypertensive rats. These results indicated a negative correlation between consumption of garlic, blood pressure and ACE activity in serum and different tissues in 2K1C rats, suggesting that garlic has a significant blood pressure lowering effect, which could partly be mediated by reduction in ACE activity.

Alteration of local ACE activity and vascular responsiveness during development of 2K1C renovascular hypertension.

OBJECTIVES: This study sought to examine the correlation between development of hypertension and local, including; aorta, heart, kidney, lung, as well as circulatory (serum) ACE activity in two kidney one clip (2K1C) renovascular hypertension. METHODS: Ten- to twelve-week-old rats undertaken left renal artery clipping. Experiments were carried out in 2, 4, 8, and 12 weeks after induction of hypertension (2, 4, 8 and 12W). After sacrificing, animals blood and tissues including heart, aorta lung and kidney were dissected out and homogenized in Trizma buffer. ACE activity was determined by hydrolysis of the synthetic substrate, Hip-His-Leu and the amount of hippuric acid liberated from the substrate were analyzed by HPLC. Vascular responsiveness was measured using perfusion pressure method. RESULTS: The systolic blood pressure (SBP) was gradually increased in 2K1C animals and was markedly higher compared to that of controls. The ACE activity in all tissues from 2K1C was significantly different in all groups of 2, 4, 8, and 12 weeks after surgery. The serum ACE activity of 2K1C was markedly increased in 2 and 4W and reached to plateau in 8 and 12W group. Vascular responsiveness to angiotensin I (AngI) was increased during development of hypertension in all groups of animals. CONCLUSION: These results indicated that there is a positive correlation between augmentation of blood pressure and local ACE activity in various tissues as well as serum, highlighting the significant contribution of local compared to circulatory ACE activity in development of renovascular hypertension.