Comparative gene expression profiling of a resistance artery taken from rats with either renin-angiotensin-dependent or glucocorticoid-induced hypertension has identified over 800 genes showing significant changes. Statistical analysis of the microarrays showed consistency in gene expression amongst the replicates within each experimental group but evidence of substantial transcriptional differences between the two hypertensive models and the normotensive controls. The majority of these differences reflected differential vascular remodeling, as confirmed by our anatomical studies, as well as activation of specific intracellular pathways. Nevertheless, arteries from both models exhibited significantly increased expression of caveolin-1, which binds a number of important signalling molecules including endothelial nitric oxide synthase , and significantly decreased expression of Rgs2 and Rgs5, which terminate the signalling of the G proteins Gq and Gi/o . Together these common effects would be expected to elevate blood pressure through augmentation of vasoconstrictor mechanisms.
Saphenous arteries from SHRs were characterised by hypertrophic remodeling, in contrast to the arteries from the ACTH rats in which no alterations were found in the number of smooth muscle cell layers. Similar changes have been described in other arteries of SHR [20, 22, 23], typical of remodeling of similarly sized resistance vessels during angiotensin II-induced hypertension . The absence of hypertrophy in the saphenous artery of ACTH-treated rats suggests that inward eutrophic remodeling  may be more common to this form of hypertension, perhaps related to the lower blood pressures experienced in comparison with those of the SHR. In the endothelium of SHR arteries, there was a significant reduction in the area of endothelial cells, consistent with changes observed in other muscular arteries of SHR [29–31]. Surprisingly, the area of endothelial cells was increased during ACTH-treatment resulting in a decrease in overall endothelial cell numbers. Changes in gene expression were consistent with cell proliferation in angiotensin II-dependent hypertension but not in glucocorticoid-induced hypertension. Thus, expression of growth promoters was upregulated and growth inhibitors suppressed in SHR arteries, while effects on both growth promoters and inhibitors were more diverse in the ACTH arteries. A lack of change in myoendothelial gap junctions suggests that these structures are not involved in the remodeling processes in saphenous arteries in either form of hypertension.
A large number of other genetic differences in the arteries from the two hypertensive models emerged from the study. These related to lipid metabolism, mitochondrial activity, calcium handling, ion transport, the adenylate cyclase pathway and protein kinase C. Not surprisingly, saphenous arteries from SHR showed upregulation of genes consistent with renin-angiotensin hypertension, and angiotensin II signaling pathways through Raf and MEK1/2 . Upregulation of growth promoters and down regulation of growth suppressors as found in the SHR samples would be expected to stimulate cell growth and proliferation, mobilise intracellular Ca2+ and reactive oxygen species [18, 32]. In contrast, the saphenous arteries from ACTH-treated animals showed upregulation of the p38MAP kinase pathway which is involved in inflammation and apoptosis, as well as growth and differentiation , accentuating mechanistic differences between the two models of hypertension. While alterations to the extracellular matrix were found in both hypertensive models, substantial changes involving multiple collagen genes were found predominantly in the ACTH model. Such changes have been linked with hypertension  and could impact on cytoskeletal signalling through integrin receptors.
Downstream mechanisms underlying smooth muscle contraction and calcium sensitization also varied between the two hypertensive models. Calcium/calmodulin-dependent protein kinase II (CaMkII) has an important role in regulating smooth muscle contractility by inhibiting myosin light chain kinase (MLCK) and the phosphorylation of myosin light chain . In SHR, upregulation of CaMkII may shift smooth muscle contraction toward Rho-dependent mechanisms and decreased phosphatase activity. In contrast, in ACTH, CaMkII was downregulated suggesting that smooth muscle contraction could be more influenced by MLCK, in addition to Rho-dependent mechanisms.
In the face of these substantial differences in gene expression between the two hypertensive models, we found coordinate upregulation in gene expression of caveolin-1 and increased caveolin-1 protein in both endothelial and smooth muscle cells. Our ultrastructural observations of increased incidence of caveolae in these sites provides strong confirmation of the immunohistochemical findings since caveolae are absent in caveolin-1 knockout mice . While some of the genetic changes in SHR relative to WKY might have arisen through decades of isolation from the parent WKY strain following inbreeding, coordinate changes in gene expression between the SHR and the ACTH-treated WKY rats cannot be attributed to such a cause. Caveolae are now recognized as important sites for colocalisation of signaling molecules, including receptor tyrosine kinases, G-protein-coupled receptors and G-proteins, and hence are critical for vascular function . The inactivation of eNOS through binding to caveolin-1 is the best characterized function for caveolae in endothelial cells , highlighting their crucial role in vascular homeostasis. Alterations to caveolae in smooth muscle cells will also impact on cell signalling and recent studies of idiopathic pulmonary arterial hypertension in humans have concluded that increased smooth muscle expression of caveolin-1 contributes to the pathophysiology of the disease through increased capacitative calcium entry . Whether upregulation of caveolin-1 in smooth muscle cells and in endothelial cells could serve to induce hypertension warrants further investigation.
In contrast to caveolin-1, the G protein regulators, Rgs2 and Rgs5, were coordinately downregulated in both SHR and ACTH saphenous arteries. These molecules terminate G protein signalling through Gq and Gi/o by activating the GTPase activity of the Gα subunit. Downregulation thus potentiates the effect of vasoconstrictors like endothelin and angiotensin II . A role in blood pressure regulation has been demonstrated for Rgs2, since knockout mice are severely hypertensive . Activation of Rgs2 occurs in resistance and conduit arteries through binding of protein kinase G, the downstream mediator of nitric oxide action [40, 41]. Interestingly, Rgs2 was also decreased in aortic smooth muscle during L-NAME-induced hypertension . Upregulation of caveolin-1 and decreased eNOS function may therefore play a role in the downregulation of Rgs2.
Less is known about a role in blood pressure regulation for Rgs5, which has been described as a marker of arterial but not venous smooth muscle cells  and is downregulated during proliferation to form atherosclerotic plaques . In contrast, upregulation of Rgs5 has been reported during neovascularisation of tumours . Rgs5 has also been identified in endothelial cells of cerebral capillaries where it was downregulated in stroke-prone SHR compared to SHR . Our results demonstrating downregulation in arteries from both SHR and ACTH rats would suggest a role in hypertension rather than proliferation since smooth muscle hypertrophy was not a feature of the ACTH model.