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Biomedical subjects

K Amann

Publications and source records attributed to K Amann.

At least 37 records · Page 2Linked to original sources
PubMed2003

Pronounced arterial collateralization was induced after permanent rat cerebral four-vessel occlusion. Relation to neuropathology and capillary ultrastructure.

The present study investigates chronic changes in cerebral arterial vessel system, microvasculature, and brain histopathology using an adult rat model based on permanent and stepwise occlusion of four cerebral vessels. Digital subtraction angiography (DSA) was performed to study chronic changes in arterial cerebral vessel system after permanent vessel occlusion. Long-lasting functional changes such as NMDA-, AMPA- and GABA(A)-receptor binding were detected in hippocampus and dentate gyrus using autoradiography. Structural changes in cerebral capillaries were investigated using light- and electron microscopy. Chronic cerebral oligemia did not cause any significant changes in the densities of excitatory glutamate and inhibitory GABA(A) receptors. By electron microscopy we could document, however, that most capillaries in vessel-occluded animals shrank, the endothelial cells were prominent with enlarged nuclei and increased cytoplasm, and the basal membrane was thickened. In contrast to the degenerative changes in brain capillaries, pronounced arterial collateralization was disclosed by DSA after chronic brain vessel occlusion. The model of chronic occlusion of four cerebral vessels is characterized by capillary degeneration and arterial collateralization proceeding in parallel. Thus, this rat model may be useful in investigations of long-lasting compensatory mechanisms contributing to cerebrovascular or neurodegenerative disorders.

Angiography, Digital Subtraction↗
PubMed2003

Hypoxia activates the human placental vascular endothelial growth factor system in vitro and in vivo: up-regulation of vascular endothelial growth factor in clinically relevant hypoxic ischemia in birth asphyxia.

OBJECTIVE: We investigated the influence of acute hypoxia on the placental vascular endothelial growth factor system in vitro and in vivo in acute birth asphyxia compared with pregnancies that were complicated by preeclampsia and with healthy control subjects. STUDY DESIGN: Messenger RNA levels for vascular endothelial growth factor, flt-1, and KDR were measured by TaqMan real-time polymerase chain reaction in human placental choriocarcinoma cells (BeWo) that were exposed to hypoxia (1% oxygen, 5% carbon dioxide, 94% nitrogen) and in placental tissue of neonates with birth asphyxia (n = 20), newborn infants of mothers with preeclampsia (n = 20), and gestational age-matched control subjects. Immunhistologically, placental vascular endothelial growth factor protein expression was compared among the groups. RESULTS: In BeWo cells, vascular endothelial growth factor, flt-1 and KDR messenger RNA increased in a time-dependent manner in response to hypoxia. In vivo, vascular endothelial growth factor/beta-actin and KDR/beta-actin messenger RNA were significantly higher in placental tissue of newborn infants with severe hypoxic-ischemic encephalopathy than with newborn infants with mild or no hypoxic-ischemic encephalopathy and control subjects. In chronic placental hypoxia (preeclampsia), vascular endothelial growth factor and both receptors were found to be up-regulated. Increased placental vascular endothelial growth factor expression was confirmed by immunohistologic examination. CONCLUSION: The vascular endothelial growth factor system is up-regulated in response to placental hypoxia and is assumed to be a potential early indicator of severe birth asphyxia.

Actins↗
PubMed2003

Laser capture microdissection and real-time PCR for analysis of glomerular endothelin-1 gene expression in mesangiolysis of rat anti-Thy 1.1 and murine Habu Snake Venom glomerulonephritis.

Molecular analysis of pathologic changes in glomeruli requires methods allowing rapid and exact detection of alterations in gene expression. Here, we analyzed endothelin-1 (ET-1) mRNA expression in mesangiolytic glomeruli during the course of a rat and murine model of mesangioproliferative glomerulonephritis (GN). A novel method combining laser capture microdissection (LCM), which permits the precise removal of selected mesangiolytic glomeruli, with a highly sensitive real-time RT-PCR technique was used. Anti-Thy 1.1. GN was introduced in male Sprague-Dawley rats (1.0 mg/kg body weight of OX-7 IV) and Habu Snake Venom GN was introduced in C57BL6 mice (habu snake venom toxin 6 mg/kg body weight IV). The degree of mesangiolysis during both GNs was analyzed using a semiquantitative scoring system. Mesangiolytic glomeruli were microdissected at different days of the diseases (day 2, 6, and 12 in anti-Thy 1.1 GN and days 1, 3, 7, and 14 in Habu Snake Venom GN) and from normal control animals. After RNA extraction and cDNA synthesis, ET-1 gene expression was measured by real-time RT-PCR. In parallel, in anti-Thy 1.1. GN ET-1 mRNA expression was analyzed using semiquantitative nonradioactive in situ hybridization; ET-1 protein expression was investigated by immunohistochemistry. Mesangiolysis peaked at day 6 in anti-Thy1.1 GN and at day 1 in Habu Snake Venom GN. Mesangiolytic glomeruli were easily microdissected on cryostat sections in both models; quantification of mRNA with RT-PCR was reliable and reproducible. Glomerular ET-1 mRNA expression increased during the course of anti-Thy 1.1 GN and Habu Snake Venom GN peaked when mesangiolysis was most pronounced. This was seen by RT-PCR after glomerular LCM and by in situ hybridization; in parallel, glomerular ET-1 protein expression was increased. Combination of LCM and RT-PCR is a reliable method for quantification of localized gene expression in isolated renal structures. The above data argue for an important role of ET-1 in pathogenesis and/or repair of mesangiolysis in experimental mesangioproliferative GN.

Animals↗
PubMed2003

Special characteristics of atherosclerosis in chronic renal failure.

Cardiovascular complications are a major clinical problem in patients with chronic kidney disease and end stage renal failure. Death from cardiac causes accounts for 40%-50% of all deaths in these patients and is thus up to 20 times more common in uremic patients than in the general population. Cardiovascular pathology in patients with renal failure is complex, but accelerated atherosclerosis has repeatedly been discussed as one major cause. The prevalence of coronary atheroma in uremic patients is approximately 30% by autopsy and coronary angiography studies. Not only is the prevalence of atherosclerotic lesions very high, but also the case fatality rate of myocardial infarction. Recently, excess mortality in uremic patients having had a myocardial infarct was noted; the one year mortality was 55.4% and 62.3% in uremic patients with and without diabetes, respectively, compared to about 10-15% in non-uremic patients. This study goes beyond the well-known notion that urea is associated with more severe atherosclerosis and shows that, in addition, the adaptation to coronary perfusion deficits is inappropriate. Recent clinical and autoptical studies in pre-dialysis and dialysis cohorts have documented increased intima and media thickness which appear early in the course of renal disease; Vascular wall thickening in renal failure seems to be modified at least in part by parathyroidhormone (PTH) and endothelin-1 (ET-1) which are both elevated in patients with renal failure. In experimental renal failure a direct effect of high phosphorus diet in arterial wall thickening was also documented. In addition to thickening of the vascular wall marked structural alterations were noted in renal failure i.e. a decrease in elastic fibre content and an increase in extracellular matrix. Furthermore, increased calcification of coronary atherosclerotic plaques and of the media of the aorta and some peripheral arteries has been documented in patients with renal failure. Factors contributing to this increased calcification process may be deposition of abundant circulating calcium, microinflammation, oxidative stress, de novo expression of bone morphogenous proteins and lack of inhibitors of calcifcation. These changes in vascular wall composition may alter vessel elasticity and thus contribute to impaired vessel function in renal failure. It is obvious from the above mentioned facts that cardiovascular disease in the renal patient is certainly multifaetorial in origin. There are, however, important issues to adress in the future, like (I) the characterization of vascular morphology in the different vascular beds, (II) the pathomechanisms of vascular and plaque calcification as well as the potential beneficial effect of rigorous control of non-classical risk factors (i.e. high P or Ca x P, inflammation, oxidative stress, etc.), (III) an additive or supraadditive effect of various classical and non-classical risk factors and (IV) the role of diabetes mellitus in modifying these vascular alterations.

Animals↗
PubMed2003

Mechanisms and consequences of sympathetic hyperactivity in renal disease.

Kidney impairment of different origins can lead within a short time to structural and functional maladaptations of the kidney, which may culminate in end-stage renal failure. The most common causes of chronic renal failure are due to hypertensive and diabetic renal impairment [Moore et al. 1999, Ritz et al. 1999]. Moreover, an inadequate blood pressure control in primary renal diseases further accelerates the decline of renal function. In spite of improved therapeutic measures the number of patients with chronic renal failure continues to increase dramatically [Mailloux and Haley 1998]. Cardiovascular morbidity and mortality in patients with chronic renal failure are extraordinarily high and are more frequent than that observed in the general population [Vita et al. 1999]. Measures, which can reduce the high incidence of cardiovascular complications, have priority in the treatment of chronic renal failure patients. ACE-inhibitors have been shown to be the best choice in this case. Until now a possible role for sympathetic hyperactivity has not been seriously considered although there is very good clinical and experimental evidence for such a role. This overview will give a summary of the currently known experimental and clinical findings about the role of the sympathetic nervous system in hypertension and renal disease and to expound possible therapeutic strategies.

Autonomic Nervous System Diseases↗
PubMed2002

Cardiovascular changes in chronic renal failure--pathogenesis and therapy.

Cardial death caused by ischemia, which is not necessarily connected with coronary arterial changes, represents the main death cause in chronic renal failure patients. The present overview article compiles the latest findings on structural and functional changes of the heart and vessels in uremia, which have a potential effect on the ischemia tolerance of the myocardium and thus help to explain the high cardiovascular mortality in chronic renal failure. The cardiovascular structural changes comprise: 1. A left ventricular myocardium hypertrophy, 2. an interstitial myocardium fibrosis and 3. changes in the myocardial microcirculation like, above all, a rarefaction of the intramyocardial capillaries with increase in the intercapillary oxygen diffusion passage and a vascular wall thickening of intramyocardial arteries. In addition, characteristic metabolic changes, like for instance a decrease of phosphates rich in energy, which contribute likewise to a heightened ischemia sensitivity of the myocardium. At the same time an involvement of extra-myocardial vascular changes is also probable in the development of the prognostically unfavorable myocardium hypertrophy in chronic renal failure. These extracardial vascular changes consist, above all, of a wall thickening of the aorta, of the peripheral arteries and veins with reduction of the share of elastic fiber, of an increase in the extracellular matrix and of a diffuse media calcification and lead to an increase in vascular stiffness and to reduction of aortal compliance.

Animals↗
PubMed2001

Differential inhibition of tumor angiogenesis by tie2 and vascular endothelial growth factor receptor-2 dominant-negative receptor mutants.

Tumor growth is angiogenesis-dependent. Current evidence suggests that vascular endothelial growth factor (VEGF), a major regulator of embryonic and hypoxia-mediated angiogenesis, is necessary for tumor angiogenesis. VEGF is expressed in tumor cells in vivo, and its tyrosine kinase receptors VEGFR-1 and VEGFR-2 are up-regulated in the tumor endothelium. A second endothelial cell-specific ligand/receptor tyrosine kinase system, consisting of the tie2 receptor, its activating ligand angiopoietin-1 and the inhibitory ligand angiopoietin-2, has been characterized. We have examined 6 human primary breast-cancer samples and 4 murine breast-cancer cell lines (M6363, M6378, M6444, M6468), transplanted into nude mice, by in situ hybridization and/or Northern analysis. Expression of angiopoietin-1, angiopoietin-2 and tie2 was compared to VEGF and VEGFR-2 expression. Human tumors expressed VEGFR-2 and tie2 but varied considerably in VEGF and angiopoietin-1/-2 expression. In the murine tumor models, we observed high heterogeneity of receptor and ligand expression. M6363 and M6378 tumors were analyzed in detail because they showed different expression of components of the tie2/angiopoietin signaling system. M6363 tumors expressed VEGF, VEGFR-2 and angiopoietin-2 but not tie2 or angiopoietin-1, suggesting activation of VEGFR-2 and inhibition of tie2 signaling pathways, whereas M6378 tumors expressed VEGF, VEGFR-2, tie2 and angiopoietin-1 but little angiopoietin-2, suggesting activation of both VEGFR-2 and tie2 signaling pathways. In vivo studies using truncated dominant-negative tie2 and VEGFR-2 mutants revealed inhibition of M6363 tumor growth by 15% (truncated tie2) and 36% (truncated VEGFR-2), respectively. In contrast, M6378 tumor growth was inhibited by 57% (truncated tie2) and 47% (truncated VEGFR-2), respectively. These findings support the hypothesis that tumor angiogenesis is dependent on VEGFR-2 but suggest that, in addition, tie2-dependent pathways of tumor angiogenesis may exist. For adequate application of angiogenesis inhibitors in tumor patients, analysis of prevailing angiogenesis pathways may be a prerequisite.

Adenocarcinoma, Mucinous↗
PubMed2001

Increased expression of endothelin-1 and inducible nitric oxide synthase isoform II in aging arteries in vivo: implications for atherosclerosis.

We here report that aging increases expression of endothelin-1 and NO synthases in the vasculature and kidney of normotensive rats in vivo. Expression of preproendothelin-1 mRNA was quantified by RT-PCR and in situ hybridization, and endothelin-1 protein was determined by radioimmunoassay/HPLC. Vascular mRNA expression of NO synthase isoforms II and III was analyzed by RT-PCR. In young animals, vascular endothelin-1 protein was differentially expressed (aorta < renal artery < carotid artery) and increased with aging in all vascular beds (P < 0.05). In the intact aorta of aged rats, mRNA expression of preproendothelin-1, "inducible" NO synthase II, and endothelial cell NO synthase III gene was up-regulated (P < 0.05). Moreover, preproendothelin-1 mRNA expression increased in glomeruli and tubulointerstitial cells (P < 0.05). To our knowledge this is the first study demonstrating local vascular up-regulation of the trophic factor endothelin under physiological conditions. Activation of vascular endothelin and NO synthases may be important, pressure-independent factors contributing to structural and functional abnormalities of age-dependent diseases, including atherosclerosis.

Aging↗
PubMed2001

Glomerulosclerosis and progression: effect of subantihypertensive doses of alpha and beta blockers.

BACKGROUND: Uremia is characterized by inadequately increased sympathetic activity. Sympathetic overactivity is involved in the genesis of hypertension in uremia, but its potential role on progression has not been well investigated. To address this issue, the effect of subantihypertensive doses of an alpha blocker and a beta blocker, and their combination on renal morphology and on albuminuria were investigated in the model of the subtotally nephrectomized rat. METHODS: Male Sprague-Dawley rats were subjected to surgical ablation (SNX) or sham operation (sham). Three days after surgery groups were treated either with phenoxybenzamine (PBZ, 5 mg/kg body weight/day), metoprolol (MET, 150 mg/kg body weight/day) or their combination (PBZ 2.5 mg/kg body weight/day + MET, 50 mg/kg body weight/day). Renal morphology was evaluated after 12 weeks by quantitative histology, immunohistochemistry, and electron microscopy. Urine albumin excretion and kidney endothelin-1 (ET-1), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-beta) mRNA expression were assessed. RESULTS: Systolic blood pressure was significantly higher in all SNX groups compared with sham-operated controls with no difference in the SNX groups. The number of glomeruli per left kidney was reduced from 30,904 +/- 3212 to 17,480 +/- 2341 by SNX (-43.5%). Mean glomerular volume increased from 2.63 +/- 0.7 in untreated sham operated to 4.11 +/- 0.48 microm 3 x 10(6) in untreated SNX (56.3%). The glomerulosclerosis index did not change in SNX + PBZ rats, but was significantly lower in SNX + MET (0.56 +/- 0.14) and particularly SNX + PBZ + MET rats (0.49 +/- 0.11) than in untreated SNX (0.74 +/- 0.24). Glomerular capillary length density (LV) as a sensitive index of capillary obliteration was significantly lower in SNX and almost normalized in the three intervention groups. The same was true for the mean podocyte number per glomerulus. Glomerular ultrastructure in SNX was largely preserved by all treatments. The albumin excretion rate was significantly higher in untreated SNX than in sham; it was significantly lower in all treated SNX groups. CONCLUSION: The beneficial effect of non-hypotensive doses of alpha and beta blockers and their combination on renal morphology and albuminuria in the model of renal ablation argue for a blood pressure-independent role of sympathetic overactivity in the genesis of progression. In addition, the beneficial effect of adrenergic receptor blockade indicates that a substantial part is not mediated by sympathetic cotransmitters such as adenosine 5'-triphosphate (ATP) and neuropeptide Y (NPY).

Adrenergic alpha-Antagonists↗
PubMed2001

An Ig mu-heavy chain transgene inhibits systemic lupus erythematosus immunopathology in autoimmune (NZB x NZW)F1 mice.

Intrinsic defects in the B lymphoid lineage are involved in predisposition for systemic lupus erythematosus in (NZB x NZW)F(1) (NZB/W) mice. In addition, a contribution of CD4(+) T cells has been shown to be crucial for the development of fatal glomerulonephritis. To further dissect the role of B and T cells in lupus immunopathology we used Ig mu-heavy chain (muHC) transgenic (Tg) NZB/W mice that we recently established to study mechanisms of B cell tolerance. The Tg NZB/W mice have a very restricted B cell repertoire and only a very minor population of B cells having endogenously rearranged muHC Ig loci are able to undergo isotype switch. Here we analyzed the influence of the restricted B cell repertoire on the development of IgG anti-DNA antibodies and glomerulonephritis as well as the hyperactivation of T(h) cells. IgG anti-DNA antibodies developed delayed but consistently in the Tg NZB/W mice, suggesting that a strong selective mechanism for the development of these autoantibodies is operative. Despite significant autoantibody titers in Tg NZB/W mice, very little immune deposits in the glomeruli and no evidence for renal inflammation were found. The Tg mice have a significantly prolonged survival time and most of the Tg mice lived much longer than 1 year. Interestingly, the generalized T cell activation that normally correlates and coincides with the progression of the disease in NZB/W mice is strongly reduced in older Tg animals. The absence of IgG3 anti-DNA antibodies and the strong reduction of IgG2a anti-DNA antibodies in the Tg mice suggests that particularly the activation of T(h)1 cells is inhibited. This result shows that a significant restriction in the B cell repertoire prevents hyperactivation of T(h) cells and supports the model that T cell hyperactivation in NZB/W mice is secondary to specific interactions with a subpopulation of presumably autoreactive B lymphocytes.

Animals↗
PubMed2001

Sympathetic overactivity and arterial hypertension in renal failure.

In the past, it had been presumed that hypertension in chronic renal disease can be explained by the dual effects of sodium retention and inappropriate activity of the renin-angiotensin system. Recent experimental and clinical data provide strong evidence that the increase in blood pressure is to a large part due to sympathetic overactivity which is triggered by afferent signals emanating from the kidney and resetting sympathetic tone by stimulation of hypothalamic centres. The sequelae of sympathetic overactivity extend beyond their effects on blood pressure and include accelerated progression of renal failure and presumably increased cardiac arrhythmia.

Adrenergic beta-Antagonists↗
PubMed2001

Endothelin in renal diseases and cardiovascular remodeling in renal failure.

The pathogenetic mechanisms leading to progression of renal failure are only partly understood. Several studies in immune- and non-immune-mediated models of renal damage have recently implicated the endothelin (ET) system as a major player in these processes. In animal models, ET receptor antagonists have been shown to be highly effective in abrogating the progression of renal failure. Furthermore, cardiac structural alterations seen in hypertension and/or renal insufficiency, e.g. left ventricular hypertrophy, thickening of intramyocardial arterioles, and the increase in non-vascular interstitial tissue, are largely prevented by ET receptor antagonists. In this context it is of interest that these beneficial renal and cardiac effects are, at least in most studies, independent of systemic blood pressure. In addition to the specific pharmacological blockade of the renin-angiotensin system [ACE inhibitors, angiotensin II receptor (AT1) antagonists], blockade of ET receptors or ET converting enzyme (ECE) may be a new tool to interfere with progression of renal failure and cardiovascular remodeling in humans.

Angiotensin Receptor Antagonists↗
PubMed2000

Endothelial dysfunction of coronary resistance arteries is improved by tetrahydrobiopterin in atherosclerosis.

BACKGROUND: Tetrahydrobiopterin (BH4), an essential cofactor for the synthesis of NO, improves endothelial dysfunction after ischemia/reperfusion. Therefore, we hypothesized that reduction of BH4 is involved in the attenuation of endothelium-dependent vasodilation in atherosclerosis, and we investigated the effect of alterations of the BH4 level on the vasodilatory potential of coronary resistance vessels from humans and pigs with atherosclerosis. METHODS AND RESULTS: Coronary arterioles were obtained from patients undergoing CABG (atherosclerosis group) or valve replacement (control group) and from pigs fed either a standard diet (control group) or atherogenic diet (atherosclerosis group). After isolation, vessels were cannulated, pressurized, and placed on the stage of an inverted microscope. Dose-response curves were investigated in response to the endothelium-dependent agonists histamine, serotonin, and acetylcholine (for pigs, substance P) and to the endothelium-independent agonist sodium nitroprusside (SNP) under control conditions and before and after incubation of the vessels with sepiapterin (substrate for BH4 synthesis). In vessels from patients and from animals with atherosclerosis, compared with vessels from the control groups, there was a significant (P:<0.05) reduction of vasodilation to all tested endothelium-dependent agonists but not to SNP. After application of sepiapterin, the responses to the endothelium-dependent agonists but not to SNP were significantly improved in vessels from the atherosclerosis groups. Sepiapterin did not influence vascular reactivity in the control groups. CONCLUSIONS: Atherosclerosis severely compromises endothelial function of coronary resistance arteries. Administration of sepiapterin leads to a significant improvement of endothelium-dependent vasodilatation to different agonists in vessels from humans and pigs with atherosclerosis. Therefore, we conclude that a reduced availability of BH4 is involved in the development of endothelial dysfunction in atherosclerosis.

Acetylcholine↗
PubMed2000

Effects of ACE inhibition and bradykinin antagonism on cardiovascular changes in uremic rats.

BACKGROUND: Cardiovascular death continues to be a major problem in renal failure. Structural abnormalities of the heart and the vasculature contribute to the increased cardiovascular risk. They are ameliorated by angiotensin-converting enzyme (ACE) inhibitors, but because of the nonspecifity of ACE inhibition, it is uncertain whether the beneficial effect is mediated by interfering with angiotensin II (Ang II) or by modulating other effector systems, for example, bradykinin. METHODS: To assess a potential role of bradykinin, subtotally nephrectomized Sprague-Dawley rats (SNX) received either the ACE inhibitor Ramipril (Rami, 0.2 mg/kg body weight p.o.), the specific B2 bradykinin receptor antagonist Hoe140 (0.2 mg/kg body weight, s.c.), or a combination of both, and were compared to sham-operated controls. To separately assess the effect of Ramipril on development and reversal of structural abnormalities, animals were either treated from the third day after SNX or from the fourth week after SNX onward (0.01 mg/kg body weight, p.o.). RESULTS: Heart and aorta were evaluated by morphometric and stereologic techniques. The weight of the perfused left ventricle, as an index of cardiac hypertrophy, was significantly higher in untreated SNX. While it was significantly lower in animals with early and late Ramipril treatment, the beneficial effect was completely antagonized by Hoe140. The wall-to-lumen ratio of intramyocardial arterioles was significantly higher in untreated SNX compared with controls, but failed to be modified by administration of either Ramipril or Hoe140. In the heart, the intercapillary distance was significantly higher in SNX, but it was not lowered by either early or late Ramipril or Hoe140 treatment. Treatment of SNX with Hoe140 alone, however, resulted in a marked further increase in intercapillary distance. The wall thickness of the aorta was significantly higher in SNX than in controls; early and late Ramipril treatment prevented such increase, and this effect was antagonized by Hoe140. CONCLUSION: These findings illustrate that bradykinin plays an important role for the beneficial effect of Ramipril in preventing (and potentially reversing) abnormal cardiovascular structure in uremic hypertensive rats.

Adrenergic beta-Antagonists↗
PubMed2000

Microvascular disease--the Cinderella of uraemic heart disease.

It has been known for a long time that atherosclerosis, particularly plaques in the epicardiac coronary conduit arteries, are more frequent in patients with chronic renal failure than in non-uraemic patients. It has been only recently, however, that modification of post-stenotic remodelling of cardiac arteries as well as abnormalities of the arterioles and the capillaries in the myocardium of uraemic animals and uraemic patients have been recognized and analysed. These lesions can be dissociated from changes in blood pressure and may be an important cause contributing to reduced ischaemia tolerance and cardiac malfunction (pump failure, arrhythmia) thus predisposing to cardiac death. Recent insights into angiogenesis, particularly adaptive angiogenesis in response to hypoxia, may potentially provide novel approaches to the understanding and management of cardiac microangiopathy in renal failure.

Animals↗