[Ca ²⁺ ] _i Reduction Increases Cellular Proliferation and Apoptosis in Vascular Smooth Muscle Cells

Abstract

Abstract-CardiovascularKey Words: cAMP Ⅲ phosphodiesterase Ⅲ proliferation Ⅲ ERK Ⅲ apoptosis A utosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations to either PKD1 or PKD2 genes encoding polycystin-1 (PC1) or polycystin-2 (PC2), respectively. PC1 is a plasma membrane receptor-like protein that has functions in cell-cell or cell-extracellular matrix interactions. PC2 is a nonselective cation channel protein with a large single-channel conductance and high permeability to calcium (Ca 2ϩ ). PC1 interacts with PC2. Their interaction can form a functional receptor-ion-channel-complex and regulate heterotrimeric G-protein-mediated signaling cascades. The mutations of either gene cause a nearly identical clinical phenotype (see review 1 ).Cardiovascular complications are the leading cause of mortality and morbidity in ADPKD. The incidence of intracranial aneurysms/aneurysmal ruptures and thoracic aortic dissections in ADPKD is approximately 10-fold higher than in the general population. 2 Even during the early stages of ADPKD, before the onset of hypertension or renal dysfunction, abnormal thickening of the intrarenal arteries and reduction in renal blood flows are evident. 3,4 Although clinical and experimental evidence indicate a close relation between PKD/Pkd mutations and vascular complications, their pathogenesis is not understood. We have shown that when induced to develop hypertension, Pkd2 ϩ/Ϫ mice have an increased susceptibility to vascular injury, manifested as premature death or developing prominent irregular thickening in the tunica media layer of intracranial vessels. 5 The areas of irregular vessel wall thickening are correlated with abnormally increased or decreased number of VSMCs, indicating an imbalance between smooth muscle cellular proliferation and apoptosis.Elevated rates of proliferation and apoptosis are the major phenotypic features of ADPKD cells; these abnormalities have been detected in multiple organ systems including kidneys, lungs, liver, heart, brain, spleen, thymus, and testis. 6,7 Recent studies suggest that reduced basal intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and elevated intracellular cyclic 3Ј:5Ј-adenosine monophosphate (cAMP) play a role in this phenotype. Cystic renal tissues have elevated intracellular cAMP. 8,9 In contrast to its growth inhibitory effect on wild-type renal epithelial cells, cAMP promotes proliferation in PKD/Pkd mutant renal epithelial cells. 10 -12 This proliferative response to cAMP can also be induced in wild-type renal epithelial cells by reducing their basal [Ca 2ϩ ] i , 13 indi-

Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases

“…Missense mutations of Pkd2 that inhibit the channel activity of PC2 (e.g., D511V) may reduce the local Ca 2+ within the cilium and activate Ca 2+ -inhibitable adenylyl cyclases, such as AC5/6. Previous observations that cAMP concentrations are elevated in Pkd2 +/− vascular smooth muscle cells and in wild-type cells in which [Ca 2+ ] i is lowered with verapamil or BAPTA-AM, further support the tight link between Ca 2+ and cAMP signaling (32).…”

Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

“…18 It is likely that alterations in intracellular Ca 2 þ homeostasis contribute to the vascular phenotype in PKD. 20,21 In this study, we show that disruption of the Pkd1 gene in these cells did not induce gross structural abnormalities in blood vessels, even not when Pkd1 was disrupted in ECs, as well. However, an increase in blood pressure in SM22-Pkd1 del/del mice, induced by angiontensin II treatment, resulted in reduced heart rate adaptation.…”

Autosomal Dominant Polycystic Kidney Disease and Intracranial Aneurysms: Is There an Increased Risk of Treatment?

“…14,15 There is evidence that the associated vascular defects in ADPCKD may be due to mutations in the PKD1 and PKD2 genes, located on the short arm of chromosomes 16 and 4. 16,17 Abnormalities of these genes in mouse models correspond with increased rates of arterial dissection, arterial rupture, and intracranial vascular abnormalities. 18 To our knowledge, only 1 study to date has investigated whether these issues engender an increased risk when treating intracranial aneurysms (whether by endovascular coiling or surgical clipping).…”