Role of Angiotensin Receptor Subtypes in Mesenteric Vascular Proliferation and Hypertrophy

Abstract

Abstract-The aim of this study was to explore the regulation of angiotensin receptors after chronic infusion with angiotensin II (Ang II) and to clarify the relative roles of the angiotensin type 1 (AT 1 ) and type 2 (AT 2 ) receptors in the mediation of Ang II-induced mesenteric vascular hypertrophy. In male Sprague-Dawley rats, Ang II infusion at a dose of 58.3 ng/min by subcutaneous osmotic minipumps for 14 days led to increased mesenteric weight and wall:lumen ratio of the vessels and proliferation of smooth muscle cells. Key Words: angiotensin II Ⅲ receptors, angiotensin Ⅲ vascular proliferation Ⅲ proliferating cell nuclear antigen T he function of angiotensin receptors in vascular proliferation and hypertrophy has been an area of ongoing debate. 1 Contradictory functions of angiotensin type 1 (AT 1 ) and type 2 (AT 2 ) receptors have been documented by several investigators both in vivo and in vitro. Angiotensin II (Ang II) may play a dual role in cultured smooth muscle and endothelial cells, 2 with the growth promoting effects of Ang II mediated by the AT 1 receptor, whereas the antiproliferative effects of Ang II occur via the AT 2 receptor. 3-5 However, several recent studies have suggested that the AT 2 receptor may act in a different manner in certain contexts. For example, Ang II-induced increase in RNA synthesis in cultured A10 smooth muscle cells, a cell line without AT 1 receptors, could be blocked by PD123319, an AT 2 receptor antagonist, but not by losartan, an AT 1 receptor antagonist, which suggests a potential trophic action of the AT 2 receptor on smooth muscle cell growth. 6 In vivo, the AT 2 receptor antagonist CGP 42112A, has been reported to be more effective at the prevention of neointima formation in an injured carotid artery model than the AT 1 receptor antagonist losartan. 7 This finding was interpreted as an indicator that the AT 2 receptor plays a predominant role in neointima formation after vascular injury. 7 However, with a transgenic technique, overexpression of the AT 2 receptor attenuates neointimal formation after balloon injury in the rat carotid artery. 8In the rat administered Ang II chronically, the relative roles of the AT 1 and AT 2 receptor in the mediation of vascular hypertrophy have been explored by several groups. Ang II-induced aortic hypertrophy and fibrosis was prevented by the AT 2 receptor antagonist PD123319 but not by the AT 1 receptor antagonist valsartan. 9 However, the opposite results have been reported by another group. 10 The difference in results between these studies is unexplained. In none of these chronic Ang II infusion studies was regulation of angiotensin receptors and in particular the AT 2 receptor explored. Therefore, the aim of the present study was to assess the regulation of angiotensin receptors after chronic infusion of Ang II alone or with either an AT 1 or AT 2 receptor antagonist. In addition, the effects of these angiotensin receptor antagonists on Ang II-associated mesenteric vascular proliferation and hypertrophy were directly eva...

Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin

“…AT1 receptor mRNA is also increased in ROP and this finding, together with our previous report that AT1-RB reduces retinal angiogenesis in ROP, 7 is consistent with AT1 and AT2 receptors having similar pro-angiogenic roles in ROP. A trophic action for both the AT1 and AT2 receptors in the retina is consistent with reports that AT1-RB and AT2-RB are anti-proliferative in proximal tubules, 16 the mesenteric arterial tree, 32 and mouse spleen lymphocytes. 41 There is also evidence that the AT2 receptor promotes cell growth and inflammation in vascular smooth muscle cells, rat embryo, and cultured cells.…”

“…Our group has previously reported that PD123319 requires continuous administration to effectively block the AT2 receptor in blood vessels and kidney using in vitro and in vivo autoradiography techniques. 16,32 By contrast, the daily administration of a single subcutaneous dose of PD123319 by Lonchampt and colleagues 40 which failed to confer retinal protection was not clearly demonstrated by that group to block the AT2 receptor in vivo. However, it must be acknowledged that the abundance of AT1 and AT2 receptors in the mouse and rat retina may also account for the discrepancies between the studies.…”

“…The chosen dose of PD123319 was based on previous autoradiographic studies by our group that have shown PD123319 to block the AT2 receptor in blood vessels and kidney. 16,32 At postnatal day 18, animals were anesthetized with pentobarbital sodium and eyes collected. Six to eight rats per group were studied.…”

Aldosterone Breakthrough During Angiotensin II Receptor Antagonist Therapy in Stroke-Prone Spontaneously Hypertensive Rats

“…19,20 However, it has also been shown that the AT2 receptor acts in concordance with the AT1 receptor in collagen synthesis in cultured vascular smooth muscle cells, 21 in proliferative effects in mesenteric artery, 22 and in smooth muscle cell growth and extracellular matrix expression in the aorta. 23 In adrenal tissues, both the AT2 receptor and the AT1 receptor are thought to stimulate aldosterone secretion.…”

Can Angiotensin II Type 2 Receptors Have Deleterious Effects in Cardiovascular Disease?

“…This study and several others that suggest either prohypertrophic or antihypertrophic effects of AT 2 are summarized in the Table. 7,[25][26][27][28][29][30] The fact that growth-promoting effects of AT 2 were not observed in earlier in vitro studies is not surprising, because AT 2 disappears rapidly in ordinary cell culture conditions. 10 However, the in vivo experiments shown in the Table appear to show that AT 2 both suppresses and promotes vascular cell growth, hypertrophy, and fibrosis, and these conflicting results are more difficult to explain.…”