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PubMed1996

Inducible nitric oxide synthase and the regulation of central vessel caliber in the fetal rat.

BACKGROUND: The purpose of this study was to evaluate the possibility that inducible nitric oxide synthase (iNOS) regulates the fetal circulation. METHODS AND RESULTS: Positive evidence for iNOS gene expression was noted in heart central vessels and placenta of untreated rat fetuses. Rats in the last week of pregnancy were treated for 5 days with L-NG-(1-Iminoethyl)lysine (L-NIL), a selective inhibitor of iNOS, at 1, 10, and 100 micrograms/mL in the drinking water. To raise NO levels, lipopolysaccharide (LPS) 30 micrograms/kg was given by intraperitoneal injection, and sodium nitroprusside (SNP) was placed in mini-osmotic pumps to deliver 10 micrograms/kg per minute. Control animals were undisturbed. On day 21 of gestation, dams were anesthetized and fetuses were delivered by cesarean section and rapidly frozen in isopentane chilled in liquid nitrogen. Frozen sections (10 microns) were used to reconstruct a computer-generated three-dimensional image of the great vessels and ductus arteriosus. Significant constriction of the great vessels and ductus arteriosus was observed with L-NIL, whereas both LPS and SNP dilated these vessels. The vasorelaxant effect of LPS was blocked by L-NIL. NO release from placental explants was 633 +/- 41 nmol/L under basal conditions, increasing to 4.0 +/- 0.4 mumol/L with LPS administration, although placental iNOS message and protein levels were unchanged. CONCLUSIONS: We suggest that nitric oxide, generated by iNOS, plays a significant role in control of major vessel and ductus arteriosus caliber in the rat fetus. In regard to the nitrergic regulation of the circulation, the fetus is clearly different from the adult.

Animals↗

PubMed2005

Remodeling of blood vessels: responses of diameter and wall thickness to hemodynamic and metabolic stimuli.

Vascular functions, including tissue perfusion and peripheral resistance, reflect continuous structural adaptation (remodeling) of blood vessels in response to several stimuli. Here, a theoretical model is presented that relates the structural and functional properties of microvascular networks to the adaptive responses of individual segments to hemodynamic and metabolic stimuli. All vessels are assumed to respond, according to a common set of adaptation rules, to changes in wall shear stress, circumferential wall stress, and tissue metabolic status (indicated by partial pressure of oxygen). An increase in vessel diameter with increasing wall shear stress and an increase in wall mass with increased circumferential stress are needed to ensure stable vascular adaptation. The model allows quantitative predictions of the effects of changes in systemic hemodynamic conditions or local adaptation characteristics on vessel structure and on peripheral resistance. Predicted effects of driving pressure on the ratio of wall thickness to vessel diameter are consistent with experimental observations. In addition, peripheral resistance increases by approximately 65% for an increase in driving pressure from 50 to 150 mm Hg. Peripheral resistance is predicted to be markedly increased in response to a decrease in vascular sensitivity to wall shear stress, and to be decreased in response to increased tissue metabolic demand. This theoretical approach provides a framework for integrating available information on structural remodeling in the vascular system and predicting responses to changing conditions or altered vascular reactivity, as may occur in hypertension.

Adaptation, Physiological↗

PubMed2006

Genome-wide linkage study of retinal vessel diameters in the Beaver Dam Eye Study.

Retinal vessels can be observed noninvasively and provide a window to microvascular systems elsewhere in the body. Generalized retinal arteriolar narrowing can represent structural changes resulting from persistent high blood pressure. However, data from recent studies also suggest that generalized retinal arteriolar narrowing might precede hypertension and contribute to its pathogenesis. To determine whether vessel diameters in the eye are genetically determined, we conducted a genome-wide linkage scan on retinal vessel diameters (central retinal artery equivalent and central retinal vein equivalent) using data from the Beaver Dam Eye Study. There were 7 regions on 5 chromosomes (3q28, 5q35, 7q21, 7q32, 11q14, 11q24, and 17q11) showing linkage signals at the nominal multipoint significance level of 0.01 for either covariate-unadjusted or -adjusted central retinal artery equivalent; there were 7 regions on 6 chromosomes (1p36, 6p25, 6q14, 8q21, 11p15, 13q34, and 14q21) showing linkage signals at the nominal multipoint significance level of 0.01 for either covariate-unadjusted or -adjusted central retinal vein equivalent. The linkage results for retinal vessel diameters indicate genetic contributions that remain significant even after adjusting for hypertension and other covariates. In summary, we provide evidence demonstrating that genetic factors independent of hypertension affect retinal vessel diameters.

Adult↗

PubMed1984

Flow into ischemic myocardium and across coronary collateral vessels is modulated by a waterfall mechanism.

If a coronary artery is ligated and the distal end cannulated, blood flows retrograde from the cannula when vented to the atmosphere. By varying the height of the outflow tubing, and thereby changing the outflow pressure, pressure-flow relationships can be constructed. We used this technique in eight dogs to assess the characteristics of blood flow into ischemic myocardium. Above a back pressure of 10 mm Hg, increasing back pressure resulted in a decrease of retrograde blood flow. However, below a back pressure of about 10 mm Hg (10.7 +/- 2.7 mm Hg), alterations in back pressure did not result in changes in retrograde blood flow (back pressure-independent region). The transition at 10 mm Hg is interpreted as the critical waterfall pressure in ischemic myocardium. In another group of eight dogs, the ischemic bed was completely embolized with 25-micron sized microspheres to prevent RBF from entering the tissue as back pressure was raised. Pressure-flow relationships performed in this group revealed a back pressure-independent region that extended to approximately 20 mm Hg (23.0 +/- 2.5 mm Hg). This behavior of the pressure-flow relationship is consistent with a waterfall phenomenon on the collateral vessels. To the extent that collateral vessels in the dog are mainly epicardial in location, the findings suggest that extravascular pressures of 20 mm Hg can occur in the more superficial layers of the heart. In addition, the waterfall on the collaterals indicates that this mechanism can operate on nonvenous vessels. Our results suggest separate waterfall phenomena operating on the collateral vessels (20 mm Hg) and on the vessels in the ischemic myocardium (10 mm Hg).

Animals↗

PubMed1988

Responsiveness of iliac collateral vessels to constrictor stimuli in atherosclerotic primates.

This study was performed to examine, first, the protective effects and responses of collateral vessels of the hind limb in normal and atherosclerotic monkeys and, second, the effects of chronic arterial occlusion on the development of atherosclerosis. The iliac artery was ligated on one side in cynomolgus monkeys. Sixteen months later, we recorded the pressure gradient across the limb collaterals and measured blood flow with microspheres. Collateral conductance was fivefold greater after chronic ligation of the iliac artery than after acute ligation. Despite dilatation or growth of collateral vessels after chronic ligation, iliac pressure was reduced distal to the ligation. Blood flow to the limb was normal after chronic ligation in both normal and atherosclerotic monkeys. Collateral vessels constricted in response to infusion of phenylephrine and serotonin in normal and atherosclerotic monkeys. Thus, one conclusion of this study is that collateral vessels restore limb blood flow to normal after chronic vascular occlusion in both normal and atherosclerotic monkeys, but the protective effects of collateral vessels may be compromised by vasoconstrictor stimuli. Morphometric measurements indicated that occlusion of the iliac artery reduced proliferation of atherosclerotic intima distal to the occlusion in the cholesterol-fed monkeys. Thus, a second conclusion of this study is that atherosclerosis is attenuated below an arterial occlusion.

Animals↗

PubMed1997

Gene transfer to cerebral blood vessels after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Vasospasm remains a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage. One step toward gene therapy to prevent spasm of cerebral vessels is to determine whether subarachnoid blood prevents transgene expression. METHODS: Vasospasm was induced in mongrel dogs using the double-hemorrhage intracranial-injection model. Diameter of the basilar artery was assessed by angiography, and profound vasospasm (> 50% decrease in diameter) was demonstrated at 4 and 7 days. Recombinant adenovirus expressing nuclear-targeted beta-galactosidase (reporter gene) under the control of the cytomegalovirus promoter was injected into the cisterna magna at the same time as (n = 9) or 2 days after (n = 4) injection of blood for induction of vasospasm. Brains were removed and examined histochemically for expression of nuclear beta-galactosidase. RESULTS: At 2 to 7 days, beta-galactosidase was expressed in leptomeninges over the brain stem, cortex, cerebral arteries, in small vessels in the cerebrum and brain stem, and in the ependymal lining of the ventricles. Transgene expression was observed in adventitia of blood vessels but not in vascular muscle or endothelium. Transgene expression was observed after simultaneous injection of virus and blood or when virus was injected 2 days after blood. CONCLUSIONS: The findings indicate that intracisternal injection of recombinant adenovirus can be used for gene transfer to cerebral blood vessels and overlying meninges, even in the presence of cisternal blood. We speculate that transfer of genes using recombinant viral vectors that encode for enzymes with vasodilator function to cerebral blood vessels and perivascular tissues may be useful for prevention or treatment of cerebral vasospasm after subarachnoid hemorrhage.

Animals↗

PubMed2003

Kinetics of retinal lipoprotein precipitation and elimination after closure of subretinal new vessels.

PURPOSE: To study the kinetics of retinal precipitation and elimination of lipoprotein in relation to photodynamic therapy of subretinal new vessels. METHODS: This was a retrospective observational study of subretinal precipitate before and after photodynamic therapy for subfoveal new vessels secondary to age-related macular degeneration in 14 eyes demonstrating precipitate at one or more visits, using digital red-free gray-scale fundus photography, intravenous fluorescein angiography, optical coherence tomography, and morphometric mapping. RESULTS: In 14 eyes of 14 patients, the area covered by lipoprotein precipitate increased from a mean of 0.54 optic disc areas (range, 0-2.61) before treatment to a mean of 0.65 optic disc areas (range, 0.01-3.04) at 45 d after treatment (P = 0.18). Eyes with a serous detachment at baseline, before the initial treatment (n = 10) demonstrated more treatment-related precipitation than eyes without a serous detachment at baseline (n = 4; P = 0.034). Two eyes with a large amount of precipitate and a long follow-up demonstrated net elimination of precipitate from approximately 100 days after the initial treatment, with uniexponential precipitate half-lives of 43 and 32 days. CONCLUSIONS: Photodynamic therapy for subfoveal new vessels may be associated with retinal precipitation of lipoprotein, presumably because early extraction of water and salts from the subretinal fluid increases the concentration of leaked plasma proteins. Despite reperfusion of the subretinal vessels, macromolecular leakage appears to cease within 100 days, indicating that functional maturation of the new vessels has occurred, with an associated decrease in pore size.

Aged↗

PubMed2003

Relationships between age, blood pressure, and retinal vessel diameters in an older population.

PURPOSE: To describe the cross-sectional relationships between age, blood pressure (BP), and quantitative measures of retinal vessel diameters in an older Australian population. METHODS: Retinal photographs from right eyes of participants (n = 3654, aged 49+ years) in the Blue Mountains Eye study taken during baseline examinations (1992-1994) were digitized. The width of all retinal vessels located 0.5 to 1.0 disc diameters from the disc margin was measured by a computer-assisted method. Summarized estimates for central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) represent average retinal vessel diameters. The arteriole-to-venule ratio (AVR) was calculated. Associations between age and BP and CRAE, CRVE, and AVR were assessed with generalized linear models. RESULTS: Retinal vessel diameters decreased with increasing age in both men and women. CRAE and CRVE decreased by 4.8 microm and 4.1 microm, respectively, per decade increase in age, after adjusting for sex and mean arterial blood pressure. Mean AVR declined by 0.01 for each increasing decade of age, until 79 years. After adjustment for age, sex, smoking, and body mass index, CRAE, CRVE and AVR were all significantly and inversely associated with BP. For every 10-mm Hg increase in mean arterial blood pressure, AVR decreased by 0.012 and CRAE and CRVE decreased by 3.5 microm and 0.96 microm, respectively. CONCLUSIONS: Retinal arteriolar and venular diameters narrow with increasing age, and these parameters are inversely related to BP, independent of age, gender, and smoking. The findings are consistent with those from the Atherosclerosis Risk in Communities Study suggesting that decreased retinal vessel diameters may reflect microvascular damage from elevated blood pressure.

Aged↗

PubMed2005

Anastomotic vessels remain viable after photodynamic therapy in primate models of choroidal neovascularization.

PURPOSE: Anastomotic vessels in exudative age-related macular degeneration (AMD) represent a serious clinical feature that reportedly does not respond well to either photocoagulation or photodynamic therapy (PDT). Anastomoses also occur in various animal models of choroidal neovascularization (CNV). In the present study, anastomotic vessels and their patency were evaluated in two primate CNV laser-trauma models after PDT, by using two novel photosensitizers. METHODS: In cynomolgus (Macaca fascicularis) and squirrel (Saimiri sciureus) monkey eyes (n = 20), matrix placement of laser photocoagulation sites elicited CNV as a component of the development of fibrovascular tissue (FVT). FVT sites received PDT according to specific drug infusion and laser light treatment parameters. FVTs and anastomoses were evaluated by fundus photography, fluorescein angiography, and histologic examination. RESULTS: Anastomoses averaged approximately 48% of FVT sites, with greatest occurrence in the macaque. Although PDT with each photosensitizer effectively produced FVT closure, both retinal vessels and anastomoses remained patent. CONCLUSIONS: Although PDT is effective in closing the choroidal neovascularization in FVT, this technique was ineffective in occluding anastomotic vessels and their associated tributaries within the mid- to proximal retina. Various factors (vascular diameter, composition, blood flow, orientation) may contribute to continued anastomotic patency. By convention, such vessels would typically be defined as chorioretinal anastomoses (CRAs); however, continuing studies suggest the possibility that these neovessels constitute dual-origin hybrids. Regardless of origin, viable anastomoses provide one potential mechanism for revascularization to occur after PDT and may help to explain why CRAs are considered a poor prognostic sign in patients with AMD.

Animals↗

PubMed2006

Time-lapse imaging of vitreoretinal angiogenesis originating from both quiescent and mature vessels in a novel ex vivo system.

PURPOSE: Diabetic retinopathy (DR) is an angiogenic disease that leads to severe visual loss. However, adequate animal models of vitreoretinal neovascularization in proliferative diabetic retinopathy (PDR) have not yet been described. The purpose of this study was to develop a novel ex vivo system for assessing vitreoretinal angiogenic processes that originate from both quiescent and mature vessels that could be observed with time-sequential imaging. METHODS: The retinas of 7- to 8-week-old mice were cultured for 4 days, with or without several growth factors with novel procedures, and immunohistochemistry was performed. The retinas from Tie2-GFP mice were cultured with vascular endothelial growth factor (VEGF), and time-sequential imaging of vitreoretinal angiogenesis was acquired. RESULTS: Vascular sprouts were induced by both VEGF and placenta growth factor, but not by insulin-like growth factor-1, basic fibroblast growth factor or angiopoietin-2. In explants with or without VEGF, perivascular mural cells were dissociated from endothelial cells, which is an important step during angiogenesis and in the progression of DR. Furthermore, use of time-lapse observations of retinal neovascularization events visualized that the first step in vascular sprout emergence from quiescent vessels was a single cell extension. The leading edges of a sprouting endothelial cell extended and retracted in a sequential manner. From newly formed vessels, additional vascular sprouts then emerged and new vessels fused to each other, resulting in vascular branching. CONCLUSIONS: Time-lapse imaging of this system visualized the dynamic process in vitreoretinal neovascularization from quiescent and mature vessels.

Animals↗

PubMed2005

Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation.

Angiopoietin (Ang) signaling plays a role in angiogenesis and remodeling of blood vessels through the receptor tyrosine kinase Tie2, which is expressed on blood vessel endothelial cells (BECs). Recently it has been shown that Ang-2 is crucial for the formation of lymphatic vasculature and that defects in lymphangiogenesis seen in Ang-2 mutant mice are rescued by Ang-1. These findings suggest important roles for Ang signaling in the lymphatic vessel system; however, Ang function in lymphangiogenesis has not been characterized. In this study, we reveal that lymphatic vascular endothelial hyaluronan receptor 1-positive (LYVE-1(+)) lymphatic endothelial cells (LECs) express Tie2 in both embryonic and adult settings, indicating that Ang signaling occurs in lymphatic vessels. Therefore, we examined whether Ang-1 acts on in vivo lymphatic angiogenesis and in vitro growth of LECs. A chimeric form of Ang-1, cartilage oligomeric matrix protein (COMP)-Ang-1, promotes in vivo lymphatic angiogenesis in mouse cornea. Moreover, we found that COMP-Ang-1 stimulates in vitro colony formation of LECs. These Ang-1-induced in vivo and in vitro effects on LECs were suppressed by soluble Tie2-Fc fusion protein, which acts as an inhibitor by sequestering Ang-1. On the basis of these observations, we propose that Ang signaling regulates lymphatic vessel formation through Tie2.

Angiopoietin-1↗

PubMed2005

Evidence for incorporation of bone marrow-derived endothelial cells into perfused blood vessels in tumors.

Recent studies have demonstrated that the cellular contribution of the bone marrow to tumor neovascularization is highly complex. In this context, the extent to which bone marrow-derived cells incorporate as bona fide endothelial (nonhematopoietic) cells into perfused tumor vessels, or any new vessels formed postnatally (vasculogenesis), is unclear. To this end, we developed models to characterize local vessel-derived and bone marrow-derived endothelial cells (BMD-ECs). Then, we characterized the BMD-ECs based on a set of endothelial markers and morphology. Finally, we quantified their contribution to perfused blood vessels in tumors using transplanted as well as spontaneous primary and metastatic tumor models. We demonstrate that BMD-ECs incorporate in perfused tumor vessels, and that this contribution varies with organ site and mouse strain.

Adenocarcinoma↗

PubMed2007

Lymphatic vessels assessment in feline mammary tumours.

BACKGROUND: The lymphatic vessels play a crucial role in a variety of human cancers since tumour cell lymphatic invasion significantly influences prognosis. It is not known if pre-existing lymphatics are enough for tumour dissemination or de novo development is necessary. VEGFR-3 is an angiogenetic mediator for both lymphatic and blood vessels during embryonic development, and only for lymphatics after birth. VEGF is a mediator of both vasculogenesis and angiogenesis, regulates the growth of lymphatics in various experimental models, and is produced in many solid tumours. CD44 mediates hyaluronic acid (HA)-dependent cell adhesion: besides promoting invasion, this interaction also supports neoangiogenesis that indirectly stimulates tumour cell proliferation. The expression of VEGF-C (Vascular Endothelial Growth Factor-C), its receptor VEGFR-3 and CD44, were studied on feline mammary samples to assess the importance of lymphangiogenesis and lymphangiotrophism in neoplasia. METHODS: Samples were taken from six normal mammary glands (NMG), ten benign (BT) and 32 malignant (MT) tumours. Immunohistochemical laminin/VEGFR-3 double stain, VEGF-C and CD44 stains were applied to 4 mum-thick sections, and their expression evaluated in intratumoral/extratumoral and intramammary/extramammary fields. RESULTS: All groups revealed a higher number of lymphatics in the extratumoral/extramammary areas. VEGF-C expression in the epithelium paralleled the number of positive vessels in the NMG, BT and MT, whereas VEGF-C higher expression was noted in the intratumoral fields only in infiltrating MT. CD44 score was lower in extratumoral than intratumoral fields in tumours and showed a significant increase in extramammary/extratumoral fields from NMG to MT. Pearson test showed a significant and inversely proportional correlation between CD44 expression and the number of lymphatic vessels with VEGFR-3 in malignant infiltrating tumours. CONCLUSION: The number of both VEGFR-3 positive and negative lymphatics in the extratumoral and extramammary stroma was significantly higher than intratumoral and intramammary fields respectively in the NMG, BT and MT. This suggests a scant biological importance of intratumoral lymphatics while their higher number is due to the concentration of existing vessels following compression of the extratumoral stroma in spite of a non demonstrable increase from NMG to MT. The tumour model employed provided no evidence of lymphangiogenesis, and metastasis in the regional lymph node develops following the spread through the pre-existing lymphatic network.

Animals↗

PubMed2004

Blunt trauma to large vessels: a mathematical study.

BACKGROUND: Blunt trauma causes short-term compression of some or all parts of the chest, abdomen or pelvis and changes hemodynamics of the blood. Short-term compression caused by trauma also results in a short-term decrease in the diameter of blood vessels. It has been shown that with a sudden change in the diameter of a tube or in the direction of the flow, the slower-moving fluid near the wall stops or reverses direction, which is known as boundary layer separation (BLS). We hypothesized that a sudden change in the diameter of elastic vessel that results from compression may lead not only to BLS but also to other hemodynamic changes that can damage endothelium. METHODS: We applied Navier-Stokes, multiphase and boundary layer equations to examine such stress. The method of approximation to solve the BL equations was used. Experiments were conducted in an aerodynamic tube, where incident flow velocity and weight of carriage with particles before and after blowing were measured. RESULTS: We found that sudden compression resulting from trauma leads to (1) BLS on the curved surface of the vessel wall; (2) transfer of laminar boundary layer into turbulent boundary layer. Damage to the endothelium can occur if compression is at least 25% and velocity is greater than 2.4 m/s or if compression is at least 10% and velocity is greater than 2.9 m/s. CONCLUSION: Our research may point up new ways of reducing the damage from blunt trauma to large vessels. It has the potential for improvement of safety features of motor vehicles. This work will better our understanding of the precise mechanics and critical variables involved in diagnosis and prevention of blunt trauma to large vessels.

Aorta↗

PubMed2006

Rhodamine-RCA in vivo labeling guided laser capture microdissection of cancer functional angiogenic vessels in a murine squamous cell carcinoma mouse model.

BACKGROUND: Cancer growth, invasion and metastasis are highly related to tumor-associated neovasculature. The presence and progression of endothelial cells in cancer is chaotic, unorganized, and angiogenic vessels are less functional. Therefore, not all markers appearing on the chaotic endothelial cells are accessible if a drug is given through the vascular route. Identifying endothelial cell markers from functional cancer angiogenic vessels will indicate the accessibility and potential efficacy of vascular targeted therapies. RESULTS: In order to quickly and effectively identify endothelial cell markers on the functional and accessible tumor vessels, we developed a novel technique by which tumor angiogenic vessels are labeled in vivo followed by Laser Capture Microdissection of microscopically isolated endothelial cells for genomic screening. Female C3H mice (N = 5) with established SCCVII tumors were treated with Rhodamine-RCA lectin by tail vein injection, and after fluorescence microscopy showed a successful vasculature staining, LCM was then performed on frozen section tissue using the PixCell II instrument with CapSure HS caps under the Rhodamine filter. By this approach, the fluorescent angiogenic endothelial cells were successfully picked up. As a result, the total RNA concentration increased from an average of 33.4 ng/ul +/- 24.3 (mean +/- S.D.) to 1913.4 ng/ul +/- 164. Relatively pure RNA was retrieved from both endothelial and epithelial cells as indicated by the 260/280 ratios (range 2.22-2.47). RT-PCR and gene electrophoresis successfully detected CD31 and Beta-Actin molecules with minimal Keratin 19 expression, which served as the negative control. CONCLUSION: Our present study demonstrates that in vivo Rhodamine RCA angiogenic vessel labeling provided a practical approach to effectively guide functional endothelial cell isolation by laser capture microdissection with fluorescent microscopy, resulting in high quality RNA and pure samples of endothelial cells pooled for detecting genomic expression.

Animals↗

PubMed1992

The expression of human chorionic gonadotropin/luteinizing hormone receptors in human endometrial and myometrial blood vessels.

hCG/human LH (hLH) receptors have recently been found in human endometrial and myometrial cells and uterine vasculature. The present study was undertaken to further corroborate the immunocytochemical evidence for the presence of vascular receptors. Northern blot and in situ hybridization analyses have revealed that human uterus contains a major 4.3-kilobase and a minor 2.6-kilobase hCG/hLH receptor mRNA transcript and that these transcripts are present in part in endometrial and myometrial vascular smooth muscle cells and vascular endothelial cells. Immunoblot and immunocytochemical analyses have revealed that human uterus also contains a single immunoreactive receptor protein, and that this receptor protein in part is present in endometrial and myometrial vascular smooth muscle and vascular endothelium. The expression of receptor mRNA and/or immunoreactive receptor protein was higher in myometrial than in endometrial blood vessels, and higher in vessels of both uterine compartments from the secretory compared to proliferative phase, postmenopause, or pregnancy. The blood vessels in omentum, broad ligament, and parametrium did not immunostain for hCG/hLH receptors. A blood vessel seen traversing through parametrium immunostained for the receptor protein only after it entered the myometrium. The blood vessels in nontarget tissues did not immunostain, whereas those in some target tissues, but not all of them, immunostained for the receptor protein. In summary, the present study demonstrates for the first time that human endometrial and myometrial vascular smooth muscle and endothelium express hCG/hLH receptor mRNA and immunoreactive receptor protein. These findings suggest that hCG/hLH may directly regulate blood flow in human uterus and other target tissues. The reproductive state dependency of uterine vascular receptors suggests that these receptors are probably regulated by other reproductive hormones.

Blood Vessels↗

PubMed2005

Stabilization of the retinal vascular network by reciprocal feedback between blood vessels and astrocytes.

Development of the retinal vasculature is controlled by a hierarchy of interactions among retinal neurons, astrocytes and blood vessels. Retinal neurons release platelet-derived growth factor (PDGFA) to stimulate proliferation of astrocytes, which in turn stimulate blood vessel growth by secreting vascular endothelial cell growth factor (VEGF). Presumably, there must be counteractive mechanisms for limiting astrocyte proliferation and VEGF production to prevent runaway angiogenesis. Here, we present evidence that the developing vessels provide feedback signals that trigger astrocyte differentiation--marked by cessation of cell division, upregulation of glial fibrillary acidic protein (GFAP) and downregulation of VEGF. We prevented retinal vessel development by raising newborn mice in a high-oxygen atmosphere, which leads, paradoxically, to retinal hypoxia (confirmed by using the oxygen-sensing reagent EF5). The forced absence of vessels caused prolonged astrocyte proliferation and inhibited astrocyte differentiation in vivo. We could reproduce these effects by culturing retinal astrocytes in a low oxygen atmosphere, raising the possibility that blood-borne oxygen itself might induce astrocyte differentiation and indirectly prevent further elaboration of the vascular network.

Animals↗

PubMed1999

Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse.

Development of a vascular system involves the assembly of two principal cell types - endothelial cells and vascular smooth muscle cells/pericytes (vSMC/PC) - into many different types of blood vessels. Most, if not all, vessels begin as endothelial tubes that subsequently acquire a vSMC/PC coating. We have previously shown that PDGF-B is critically involved in the recruitment of pericytes to brain capillaries and to the kidney glomerular capillary tuft. Here, we used desmin and alpha-smooth muscle actin (ASMA) as markers to analyze vSMC/PC development in PDGF-B-/- and PDGFR-beta-/- embryos. Both mutants showed a site-specific reduction of desmin-positive pericytes and ASMA-positive vSMC. We found that endothelial expression of PDGF-B was restricted to immature capillary endothelial cells and to the endothelium of growing arteries. BrdU labeling showed that PDGFR-beta-positive vSMC/PC progenitors normally proliferate at sites of endothelial PDGF-B expression. In PDGF-B-/- embryos, limb arterial vSMC showed a reduced BrdU-labeling index. This suggests a role of PDGF-B in vSMC/PC cell proliferation during vascular growth. Two modes of vSMC recruitment to newly formed vessels have previously been suggested: (1) de novo formation of vSMC by induction of undifferentiated perivascular mesenchymal cells, and (2) co-migration of vSMC from a preexisting pool of vSMC. Our data support both modes of vSMC/PC development and lead to a model in which PDGFR-beta-positive vSMC/PC progenitors initially form around certain vessels by PDGF-B-independent induction. Subsequent angiogenic sprouting and vessel enlargement involves PDGF-B-dependent vSMC/PC progenitor co-migration and proliferation, and/or PDGF-B-independent new induction of vSMC/PC, depending on tissue context.

Actins↗