Published online before print October 8, 2007, doi: 10.1161/HYPERTENSIONAHA.107.096289
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(Hypertension. 2007;50:1057.)
© 2007 American Heart Association, Inc.
Original Articles |
Axl Mediates Vascular Remodeling Induced by Deoxycorticosterone Acetate–Salt Hypertension
From the Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester, NY.
Correspondence to Vyacheslav "Slava" A. Korshunov, University of Rochester, Aab Cardiovascular Research Institute, 601 Elmwood Ave, Box 679, Rochester, NY 14642. E-mail Slava_Korshunov{at}URMC.rochester.edu
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Abstract |
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Axl, a receptor tyrosine kinase, was recently identified as a novel candidate gene in a genetic model of salt-sensitive hypertension (Sabra rat). Our group first reported that Axl plays a significant role in vascular remodeling in response to injury. Here we investigated the role of Axl in the pathogenesis of hypertension in a deoxycorticosterone acetate (DOCA)–salt model. Hypertension was induced in Axl wild-type (Axl+/+) mice and Axl-deficient (Axl–/–) mice by uninephrectomy and DOCA-salt for 6 weeks. Controls were uninephrectomized and received tap water and regular chow ad libitum. DOCA-salt treatment increased systolic blood pressure by 25 mm Hg in both genotypes after 1 week. Systolic blood pressure remained significantly elevated in Axl+/+ DOCA, whereas systolic blood pressure levels in Axl–/– DOCA mice were the same as controls at 6 weeks. DOCA-salt increased relative kidney weight and glomerular hypertrophy by 40% compared with controls in both genotypes. Consistent with levels of systolic blood pressure, endothelium-dependent vasorelaxation was impaired in Axl+/+ DOCA mice compared with Axl+/+ controls, whereas in Axl–/– DOCA mice relaxation responses were similar to Axl–/– controls. In addition, endothelium-independent vasorelaxation was improved in Axl–/– DOCA mice compared with Axl+/+ DOCA mice. Nitrotyrosine and phospho-Akt immunoreactivity was significantly reduced in arteries from Axl–/– DOCA mice compared with Axl+/+ DOCA mice. The remodeling index of the mesenteric artery (media:lumen ratio) was significantly increased in Axl+/+ DOCA mice compared with Axl–/– DOCA mice. Finally, increased vascular apoptosis in the Axl–/– DOCA mice suggests a likely mechanism for Axl-dependent effects on hypertension. These data strengthen the pathogenic role for Axl in salt-sensitive hypertension.
Key Words: Axl • mouse • hypertension • endothelial dysfunction • remodeling • apoptosis
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Introduction |
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Salt-sensitive hypertension is characterized by endothelial dysfunction associated with increases in reactive oxygen species and local renin-angiotensin-aldosterone system activation.1–3 In both spontaneously hypertensive rat and deoxycorticosterone acetate (DOCA)–salt hypertension models, reactive oxygen species production increases because of an increase in reduced NADPH oxidase activity.4,5 Thus, complex interactions among the vascular renin-angiotensin-aldosterone system, reactive oxygen species, and other factors contribute to vascular remodeling in hypertension. Recently, 7 new candidate genes (TcTex1, Myadm, Lisch7, Axl-like, Fah, PRC1-like, and Sephrinh1) were identified within the boundaries of quantitative trait loci (SS1a and SS1b) in the Sabra hypertension model using an integrated genomic-transcriptomic approach.6 Intriguingly, none of these genes had been directly associated with hypertension previously. However, our group discovered that Axl plays a significant role in vascular remodeling in response to mechanical and hemodynamic stimuli.7–9
Axl is a receptor tyrosine kinase (also known as Ufo and Tyro7) that belongs to a family of tyrosine receptors including Tyro3 (Sky) and Mer (Tyro12).10,11 A common ligand for the Axl family is Gas6 (growth arrest–specific protein 6).11,12 Increases in Gas6 and Axl family receptors are highly regulated in various pathophysiological conditions.13–16 Important cellular functions of the Gas6-Axl pathway include cell adhesion, migration, phagocytosis, and inhibition of apoptosis.17–20 We reported recently that activation of Akt is a major downstream target for the prosurvival Gas6-Axl pathway in vascular smooth muscle cells (VSMCs).8,21 Several lines of evidence suggest that upregulation of the Gas6-Axl pathway is important for experimental kidney diseases.22–26 Furthermore, activation of Gas6 and Axl by angiotensin II appears significant and has been shown to depend on NADPH oxidase in VSMCs and mesangial cells.27
Based on the significant vascular roles described for Axl, we hypothesized that Axl plays an important role in hypertension. We studied Axl wild-type and knockout mice in a DOCA-salt mouse model of hypertension. Here we report that Axl contributes to the later stages of DOCA-salt hypertension, vascular endothelial dysfunction, and remodeling via inhibiting vascular apoptosis. In contrast, early increases in blood pressure (1 to 4 weeks) and kidney hypertrophy were not affected by Axl-dependent pathways in the DOCA-salt model.
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Methods |
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An expanded Methods section is available in the online data supplement (available at http://hyper.ahajournals.org).
Animals
Axl wild-type (Axl+/+) and Axl knockout (Axl–/–) littermate mice (10 to 12 weeks old) were used in accordance with the guidelines of the National Institutes of Health and American Heart Association for the care and use of laboratory animals (approved by the University of Rochester Animal Care Committee). To genotype animals, DNA was isolated from tails at weaning, and PCR was performed.7
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Results |
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Hemodynamic Changes in DOCA-Salt Axl Mice
As we reported recently,9 there was no difference in systolic blood pressure (SBP) among Axl genotypes at baseline (mm Hg): Axl+/+ uninephrectomized (Nephr)=122±3; Axl+/+ uninephrectomized and DOCA-salt (Nephr+DOCA)=122±2; Axl–/– Nephr=125±2; and Axl–/– Nephr+DOCA=126±2. However, the SBP of Axl+/+ Nephr+DOCA mice was 25 mm Hg greater than Axl+/+ Nephr controls beginning at week 1 and persisting for a 6-week time course (Figure 1). In contrast Axl–/– Nephr+DOCA mice SBP levels were the same as Axl–/– controls at 5 weeks (compare open triangles and open squares in Figure 1). There were no differences in the heart rate among experimental groups between genotypes (Supplemental Figure S1, available at http://hyper.ahajournals.org). Hemodynamic changes that were seen in Axl+/+ Nephr+DOCA mice compared with their controls were similar to those reported previously.28,29
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P<0.05 vs Axl–/–, Nephr; 
P<0.05 vs Axl+/+, Nephr+DOCA (ANOVA).
Right Kidney Remodeling in DOCA-Salt Axl Mice
As shown previously,28,29 Nephr+DOCA increased the relative right kidney weight by 30% in Axl+/+ compared with Nephr (Figure S2A). However, there were no differences in heart or spleen hypertrophy after DOCA-salt in Axl+/+ (Figure S3A and S3B). Surprisingly, there were no differences in kidney hypertrophy among Axl genotypes (Figure S2A). Glomerular morphometry was not different between Axl genotypes after Nephr (Figure S2C and S2D). As was shown for kidney hypertrophy (Figure S2A), glomerular area was equally increased in both Axl genotypes after Nephr+DOCA compared with an appropriate Nephr control (Figure S2C). However, glomeruli cell number was slightly increased (
10%) in Axl–/– Nephr+DOCA compared with Axl+/+ Nephr+DOCA or their Nephr controls (Figure S2D). These data suggest that Axl contributes to DOCA-salt hypertension during later time points (5 to 6 weeks) without significant effects on kidney remodeling.
Aorta Vasoreactivity in DOCA-Salt Axl Mice
Endothelial dysfunction is a well-established feature of the DOCA-salt hypertension in rats.5 To assay effects of Axl on vascular function, we compared vasoreactivity of thoracic aortas from Axl mice after 6 weeks of DOCA-salt with that in Nephr mice. There were no differences in vasoreactivity responses between aortic rings from Axl+/+ and Axl–/– Nephr mice (compare open versus black squares in Figure 2). However, consistent with higher SBP values, Axl+/+ Nephr+DOCA exhibited increased maximal vasoconstriction responses (data not shown) and increased sensitivity (measured by ED50) to potassium chloride and phenylephrine (black triangles versus black squares, Figure 2A and 2B). Vasoconstriction responses in Axl–/– Nephr+DOCA mice were similar to Axl+/+ Nephr+DOCA mice (compare open versus black triangles, Figure 2A and 2B).
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Importantly, higher levels of SBP in Axl+/+ Nephr+DOCA mice (Figure 2C, black triangles) were associated with impairments in acetylcholine-mediated endothelium-dependent vasorelaxation (Figure 2C) with no effect on sodium nitroprusside–mediated, endothelium-independent vasorelaxation compared with Axl+/+ Nephr mice (Figure 2D). In addition, sensitivity to acetylcholine was significantly reduced in Axl+/+ Nephr+DOCA mice compared with Axl+/+ Nephr mice (Figure 2C). Remarkably, both endothelium-dependent vasorelaxation and sensitivity to acetylcholine in Axl–/– Nephr+DOCA mice were similar to their Nephr controls (compare open triangles versus open squares, Figure 2C). In addition, endothelium-independent vasorelaxation was improved in Axl–/– Nephr+DOCA mice compared with Axl+/+ Nephr+DOCA mice (compare open versus black triangles, Figure 2D). These data confirm the critical role for Axl in vascular alterations in DOCA-salt hypertension.
Vascular Remodeling in DOCA-Salt Axl Mice
To gain insight into the mechanisms by which Axl mediates vascular dysfunction in the DOCA-salt hypertension, we evaluated histology of the aortas and mesenteric arteries. The DOCA-salt increases in SBP correlated with vascular wall thickening. Individual areas of the components of the mesenteric artery and thoracic aorta were not statistically different between controls (Table S1). The most significant change caused by DOCA-salt hypertension was the increase in media in aorta compared with controls, whereas there was a tendency for an increase in media area in mesenteric artery in Axl+/+ mice (Table S1). However, Axl–/– Nephr+DOCA mice exhibited a significant increase in aorta lumen and showed a similar trend in the mesenteric artery lumen compared with Axl–/– Nephr mice (Table S1). The remodeling index (media:lumen ratio) in the mesenteric artery was significantly increased in Axl+/+ Nephr+DOCA mice compared with Axl+/+ Nephr mice (compare black versus open bars, Figure 3A). In contrast, the media:lumen ratio was not different between Axl–/– Nephr+DOCA and Axl–/– Nephr mice (Figure 3A). These data suggest that Axl is an important mediator of the vascular remodeling and vascular relaxation in DOCA-salt hypertension.
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Vascular Apoptosis in DOCA-Salt Axl Mice
Among the many cellular functions of Axl, apoptosis is particularly important for vascular adaptations in vitro and in vivo.7–9 ApopTag staining in the media of the mesenteric arteries was similar between Axl genotypes of Nephr mice, whereas Nephr+DOCA increased staining (data not shown). The relative number of ApopTag+ cells was similar in controls of both Axl genotypes (open bars, Figure 3B). As reported in the rat model of DOCA-salt hypertension,30 Axl+/+ Nephr+DOCA mice exhibited significantly increased apoptosis (1.5-fold) compared with Axl+/+ Nephr mice (black versus open bars, Figure 3B). However, apoptosis was even greater (2-fold) in Axl–/– Nephr+DOCA mice compared with their controls (Figure 3B). Taken together, these data indicate that Axl is involved in pathways associated with inhibition of apoptosis in hypertensive vasculature.
Immunohistochemistry of the Arteries From the DOCA-Salt Axl Mice
Increased phosphorylation of Akt expression in carotid arteries was blunted in Axl–/– compared with Axl+/+ mice after low blood flow.9 Similarly, phosphorylation of Akt immunoreactivity was dramatically reduced in the thoracic aortas and mesenteric arteries from Axl–/– Nephr+DOCA mice compared with Axl+/+ Nephr+DOCA mice (open arrows, brown staining, compare Figure 4D versus 4C). There are no differences in the phosphorylation of Akt expression in arteries from Nephr between genotypes (Figure 4A and 4B). We observed similar Gas6 immunointensity in the aortas and mesenteric arteries from mice of both Axl genotypes after Nephr+DOCA (Figure S4A and S4B). Finally, greater nitrotyrosine immunoreactivity in the media of the aortas and mesenteric arteries was evident in Axl+/+ Nephr+DOCA compared with Axl–/– Nephr+DOCA mice (brown staining in the area between brackets, compare Figure 4G versus 4H). However, there are no differences in the nitrotyrosine expression of arteries from Nephr mice between genotypes (Figure 4E and 4F). Taken together, these data suggest that Akt activity is important for vascular dysfunction and oxidative stress in hypertension.
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Discussion |
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The major conclusion of this study is that Axl, a receptor tyrosine kinase, plays an important role in vascular remodeling associated with DOCA-salt hypertension. First, we showed that SBP levels in Axl–/– Nephr+DOCA mice were the same as in Axl–/– control mice at 5 weeks (Figure 1), whereas SBP increases that were seen in Axl+/+ Nephr+DOCA mice compared with their controls were similar to those reported previously.28,29 Second, Axl participates in the SBP rise during later time points (5 to 6 weeks) without significant effects on kidney remodeling in DOCA-salt hypertension (Figure S2). Third, endothelium-dependent vasorelaxation was significantly improved in Axl–/– Nephr+DOCA mice compared with wild-type mice on DOCA-salt suggesting that Axl significantly contributed to vascular dysfunction in hypertension (Figure 2). Fourth, vascular remodeling of the mesenteric arteries was significantly reduced in Axl–/– Nephr+DOCA mice compared with that in Axl+/+ mice (Figure 3). Fifth, augmented vascular apoptosis in Axl–/– Nephr+DOCA mice is a likely mechanism for Axl-dependent effects in hypertension as we showed recently in flow-induced remodeling.9 Finally, the lack of Axl resulted in dramatic inhibition of Akt activity and reduction of nitrosative stress in the arteries from DOCA-salt mice (Figure 4).
Salt sensitivity is associated with almost half of the hypertension cases in humans.31 Salt-sensitive hypertension is traditionally believed to be "a volume-dependent hypertension" with low plasma renin levels. However, recent studies of rat DOCA-salt and genetic (Dahl) models suggest the importance of peripheral vascular changes in salt-sensitive hypertension.2,3,5,32 In particular, local activation of NADPH oxidase by vasoactive hormones (eg, angiotensin II and endothelin-1) promotes vascular inflammation and remodeling in the low-renin salt-sensitive hypertension.3,33 Given the complexity of salt-induced hypertension, genetic mapping of the 2 major rat models (Dahl and Sabra) has yielded a large number of hypertension-related quantitative trait loci. Recently, 7 candidate genes, including Axl-like, were identified within the boundaries of quantitative trait loci (SS1a and SS1b) in the Sabra model using an integrated genomic-transcriptomic approach.6 Our group discovered that Axl plays a significant role in vascular remodeling in response to mechanical and hemodynamic stimuli.7–9 The present study further supports genetic findings in the Sabra rat model based on significant reduction of the SBP level in Axl–/– Nephr+DOCA mice compared with Axl+/+ Nephr+DOCA mice (Figure 1).
Activation of autocrine growth mechanisms is a central feature of VSMC responses in vascular pathophysiology.34 In particular, we propose 3 levels of activation of VSMCs by angiotensin II: (1) fast: G protein–coupled receptors (type 1 angiotensin II receptor, endothelin-1 type A, etc) result in activation of kinases and phosphotases, which lead to rapid responses; (2) medium: trans-activation of the tyrosine kinase–coupled receptors (epidermal growth factor receptor and platelet-derived growth factor receptor) that result in autophosphorylation and downstream signal transduction, which is probably mediated by reactive oxygen species; and (3) slow: induction of other growth factors (platelet-derived growth factor, endothelin-1, fibroblast growth factor, interleukin-6, etc) and growth factor receptors (platelet-derived growth factor receptor and Axl) involved in autocrine growth pathways mediate pathophysiological adaptations of the arteries. Autocrine regulation of prosurvival pathways in VSMCs is likely of great importance for vascular remodeling in hypertension. For example, activation of the Gas6-Axl pathway increased migration and survival of VSMCs.35 We showed that the Gas6-Axl-phosphatidylinositol 3-kinase-Akt pathway inhibited VSMC apoptosis in vitro.21 Among several growth factors, angiotensin II increased Axl mRNA expression via the type 1 angiotensin II receptor in VSMCs.7 In addition, we also found that H2O2 rapidly stimulated Axl tyrosine phosphorylation in VSMCs.8 Interestingly, Axl tyrosine phosphorylation was partly dependent on production of its endogenous ligand, Gas6. Phosphorylation of Axl by H2O2 was also attenuated by warfarin, which inhibits Gas6 activity by preventing posttranslational modification. In intact vessels, Axl was phosphorylated by H2O2, and Axl tyrosine phosphorylation was inhibited by warfarin treatment in rat balloon-injured carotid arteries. Akt, a downstream target of Axl, was phosphorylated by H2O2 in Axl+/+ mouse aorta but significantly inhibited in Axl–/– aorta. Our recently published data suggest that Axl is involved in low flow–dependent vascular remodeling via inhibition of apoptosis.9 Similarly, in a mouse DOCA-salt model, we now show that the Gas6-Axl antiapoptotic pathway is important for hypertension (Figures 3 and 4
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A major limitation of the present study is that we were unable to quantitatively evaluate apoptosis of endothelial cells in the cross-sections of mesenteric arteries to elucidate the role of Gas6-Axl in endothelial cells apoptosis in hypertension. Previously, increases in apoptosis of microvascular endothelial cells after simvastatin treatment markedly reduced severe pulmonary hypertension in rats.36 Finally, future studies will be needed to clarify the specific mechanism(s) of interactions between the Gas6-Axl pathway and endothelial NO synthase during hypertension.
It was proposed recently that 3 major classes of antihypertensive drugs (eg, angiotensin II type 1 receptor blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers) induce regression of hyperplasia via induction of apoptosis.37,38 Experimental studies in VSMCs suggested that these drugs could activate a common intracellular pathway of cell death via triggering of Fas translocation and apoptosis activation.39 To date, only 1 study showed an increase in vascular apoptosis in the rat model of DOCA-salt hypertension.30 Furthermore, beneficial effects of endothelin-1 antagonists on blood pressure and remodeling have been suggested to involve increased vascular apoptosis in a rat DOCA-salt hypertension model.30 Our observations in mice support findings in the rat DOCA-salt model and suggest that inhibition of autocrine prosurvival pathways (eg, Gas6-Axl) may be a novel concept for antihypertensive therapies.
Perspectives
This is the first study to confirm recent findings of the genetic Sabra rat model of salt-sensitive hypertension that Axl, a receptor tyrosine kinase, plays an important role in vascular remodeling in hypertension. We showed that Axl participates in the SBP rise during later time points of hypertension (5 to 6 weeks), vascular endothelial dysfunction, and increases in remodeling index. Increased vascular apoptosis in Axl–/– DOCA mice suggests a possible mechanism for Axl-dependent effects on hypertension. However, early rises in SBP (1 to 4 weeks) and kidney hypertrophy were not affected by Axl-dependent pathways in a mouse DOCA-salt model. Importantly, our findings suggest that inhibition of autocrine prosurvival pathways (eg, Gas6-Axl) with Akt as a downstream target may be a novel concept for antihypertensive therapies.
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Acknowledgments |
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We thank Sarah Mack for help with histochemistry.
Sources of Funding
V.A.K. is an American Heart Association Scientist Development Grant awardee (0430267N). M.D. was supported by funds from the Office of Medical Education Research Award (the University of Rochester School of Medicine and Dentistry, Rochester, NY). This study was also supported in part by National Institutes of Health grant HL-62826 to B.C.B.
Disclosures
None.
Received June 12, 2007; first decision July 8, 2007; accepted September 11, 2007.
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