Diabetes is a chronic health condition that causes multiple vascular complications, such as retinopathy and nephropathy ^[1][23]. Pericyte loss is an early hallmark of diabetes-associated microvascular diseases and plays a crucial role in the disease progression of various organs including the retina, kidney, brain, and heart ^[1][2][23,24].

DR, a major complication of diabetes, is the leading cause of blindness worldwide and is characterized by vascular damage in the retina ^[3][4][5][25,26,27]. Among the vascular cells, pericytes are the earliest to be affected by diabetes, and their loss is a hallmark of diabetic retinopathy, contributing to blood vessel leakage ^[6][28]. The loss of pericytes has been detected in the retinas of diabetic patients ^[7][8][9][29,30,31], as well as in various animal models, including mice ^[9][10][11][31,32,33], dogs ^[12][13][34,35], hamsters ^[14][36], and rats ^[15][16][37,38].

The precise mechanisms underlying pericyte loss in diabetic retinopathy are not yet fully understood. One hypothesis suggests that pericyte death via apoptosis is involved, as confirmed by studies in both patients and animal models of DR ^{[8][10][17][18][19][20]}[30,32,39,40,41,42]. Mechanically, factors such as high-glucose ^[18][21][40,43], oxidative stress ^[22][44], advanced glycation end products ^[23][24][45,46], TNF-α ^[25][47], and IL-1β ^[26][48] have been shown to induce apoptosis in retinal pericytes in vitro and/or in vivo. Additionally, the migration of retinal pericytes may contribute to pericyte loss in DR, regulated by the Ang-Tie system and autophagy processes ^[27][28][49,50]. Pericyte loss contributes to EC-pericyte dissociation and vascular dysfunction as retinal capillary pericytes are critical to maintaining EC-pericyte contacts and the integrity of vascular barrier function via secretion of sphingosine 1-phosphate ^[29][30][51,52]. Therefore, preventing the loss of retinal pericytes would be beneficial. Pericytes derived from adipose-derived stem cells (ASCs) showed protective effects against capillary loss in the retina in a murine model of DR ^[31][53].

As a common complication of diabetes, DN is characterized by proteinuria, microvascular damage, and the disruption of glomeruli and the tubular system ^{[1][32][33][34]}[4,23,55,56]. It significantly impacts the quality of life of diabetic patients and is the leading cause of end-stage renal disease ^[1][34][23,56]. Renal pericyte-like cells, including peritubular pericytes, mesangial cells, and podocytes, are susceptible to oxidative stress induced by high glucose and play a critical role in the progression of DN ^[1][32][4,23].

Several hallmark features of DN, such as peritubular capillary rarefaction (PTC) and peritubular fibrosis, mesangial and glomerular hypertrophy, and podocyte injury, are closely associated with renal dysfunction ^{[32][33][35][36][37]}[4,55,57,58,59]. Peritubular pericytes are crucial for maintaining the integrity of peritubular capillaries, as the loss of pericytes can accelerate PTC rarefaction ^[36][38][39][58,60,61]. Furthermore, the migration of peritubular pericytes away from the capillaries and their transformation into myofibroblasts are potential mechanisms underlying PTC and peritubular fibrosis ^[32][40][41][4,62,63]. However, the precise role and underlying mechanisms of peritubular pericytes in DN remain largely unknown. Mesangial cells, comprising approximately 30% of glomerular cells, undergo hypertrophy in the early stages of DN ^{[1][32][42][43]}[4,23,64,65]. Increased mTOR activity may contribute to mesangial cell hypertrophy under high glucose conditions ^[32][43][4,65]. Moreover, diabetic rats and mice exhibit glomerular cell loss and apoptosis, which are associated with albuminuria and renal dysfunction ^[44][45][66,67]. Mechanistically, elevated levels of urinary miR-15b-5p have been observed in diabetic patients and db/db mice and contribute to high glucose-induced mesangial cell apoptosis ^[46][68]. Additionally, serum levels of Angpt2 were increased in diabetic patients and db/db mice, and the Angpt2/miR-33-5p/SOCS5 signaling pathway has been implicated in mesangial cell apoptosis under high glucose conditions ^[47][69].

Diabetes can induce damage that leads to dysfunction of the BBB and cognitive decline in both patients and experimental models ^{[48][49][50][51]}[87,88,89,90]. Furthermore, diabetic patients have a higher risk of developing dementia-related diseases such as stroke and Alzheimer’s disease (AD) ^[52][53][91,92]. In the brain, diabetes-related complications are characterized by pericyte loss, increased BBB permeability, and neuronal dysfunction ^[48][50][54][87,89,93]. Reduced numbers of brain pericytes have been reported in diabetic patients ^[1][55][23,94], as well as in animal models of diabetes, including mice and rats ^[56][57][58][95,96,97]. In vitro studies have shown that oxidative stress induced by high glucose can lead to apoptosis in cultured brain pericytes ^{[59][60][61][62]}[98,99,100,101]. The activity of mitochondrial carbonic anhydrases was believed to induce brain pericyte loss in diabetic mice as the inhibition of mitochondrial carbonic anhydrases activity can reduce oxidative stress and prevent pericyte dropout ^[57][96]. However, the exact mechanisms and in vivo processes underlying brain pericyte loss in diabetes require further investigation.

Cardiovascular disease (CVD) is a significant complication of diabetes and is the leading cause of heart failure or mortality in diabetic patients ^{[63][64][65][66]}[102,103,104,105]. Pericytes play a crucial role, particularly in the early stages of diabetes-associated CVD, including myocardial and interstitial fibrosis ^[66][67][68][105,106,107]. The loss of pericytes has been demonstrated in the hearts of diabetic patients and diabetic pigs ^[69][108]. Additionally, studies by Tu et al. showed a reduction in the number of cardiac pericytes and microvascular coverage in diabetic mice ^[2][24]. The overexpression of thymosin beta 4 has the ability to mitigate cardiac pericyte loss in diabetic pigs, providing a potential therapeutic approach for diabetes-associated CVD ^[69][108]. However, the specific underlying mechanisms of cardiac pericyte loss in diabetes remain unclear and require further investigation.

In summary, pericyte loss is closely associated with various complications of diabetes and significantly contributes to disease development. Further research is needed to gain a better understanding of the underlying mechanisms involved and to explore novel therapeutic strategies targeting pericytes.

AD is the most prevalent neurodegenerative disorder characterized by cognitive impairment, an accumulation of amyloid β-peptide (Aβ), BBB dysfunction, and neuroinflammation ^[70][71][72][109,110,111]. Pericytes play a critical role in AD, as their deficiency in mouse models of AD accelerates BBB breakdown and increases Aβ accumulation in the brain ^[73][112]. Pericyte loss has been reported in various regions of AD patients’ brains, including the white matter ^[74][75][113,114], precuneus ^[76][115], cortex ^[73][77][112,116], hippocampus ^[77][78][7,116], and retina ^[79][117]. Similarly, reduced pericyte numbers have been observed in the cortex ^[80][81][118,119], hippocampus ^[78][81][7,119], and retina ^[82][120] of AD mice. In the retina, the activation of inflammation appears to contribute to pericyte loss as an association between NF-κB p65 phosphorylation levels and vascular PDGFRβ expression was observed in AD mice ^[82][120]. Apoptosis is believed to contribute to pericyte loss, as pericyte apoptosis has been identified in the retina and hippocampus of AD patients ^[78][79][7,117]. In vitro studies have shown that Aβ stimulation induces apoptosis in cultured brain pericytes ^[78][81][7,119]. Mechanistically, decreased miR-181a levels and enhanced Fli-1 expression may contribute to pericyte loss and apoptosis in AD ^[78][81][7,119]. A reduced miR-181a expression has been observed in AD mice, but the overexpression of miR-181a can mitigate pericyte loss, improve BBB function, and decrease Aβ accumulation ^[81][119]. Furthermore, miR-181a inhibits Aβ-induced pericyte apoptosis in murine brain cell cultures ^[81][119].

ALS, a fatal neurodegenerative disorder, is characterized by blood–spinal cord barrier dysfunction and the progressive degeneration of motor neurons ^{[83][84][85][86]}[125,126,127,128]. Recent studies have highlighted the important role of pericytes in ALS ^[87][129]. Decreased pericyte coverage or number has been observed in the ventral horn and spinal cord of ALS patients, which correlates with vascular disruption ^[88][89][130,131]. Furthermore, a loss of pericytes in the choroid plexus has been detected in patients with ALS, coupled with a deregulation of the blood–cerebrospinal fluid (CSF) barrier ^[90][132]. In a murine model of ALS, reduced pericyte coverage in spinal cord capillaries has also been demonstrated ^[91][133]. Interestingly, the administration of adipose-derived pericytes has shown promising results in ALS mice, extending their survival and increasing antioxidant enzymes in the brain ^[92][134]. These findings suggest that pericytes may represent a novel potential cell therapy for treating ALS, although further studies are needed to fully understand pericyte loss in ALS and its implications for disease progression.

Overall, pericyte loss in aging and neurodegenerative diseases poses a significant challenge that can have negative effects on brain health. Advancing the understanding of the underlying mechanisms of pericyte loss and developing new treatments to prevent or reverse this process are important areas of future research.

Sepsis is a life-threatening condition caused by a microbial infection resulting in organ dysfunction and failure. It is characterized by a systemic inflammatory response and microvascular dysfunction ^[93][94][135,136]. Recent studies have highlighted the role of dysfunctional pericytes in sepsis-induced microvascular dysfunction, which serves as a hallmark of severe sepsis and septic shock ^[95][96][15,137]. Research by Nishioku et al. demonstrated the detachment of pericytes from the basal lamina in the hippocampus of LPS-treated mice ^[97][138]. The detachment of pericytes may contribute to sepsis-induced BBB dysfunction ^[98][139] as pericytes control vascular permeability in the brain ^[99][140]. Pericyte loss has also been observed in the lungs and hearts of LPS-treated mice, although this loss is not caused by apoptosis ^[100][141]. Reduced pericyte coverage in mesenteric microvessels has been demonstrated in both cecal ligation and puncture (CLP) and LPS-induced septic rats ^[101][142].

The neurocognitive disorder is a major complication of HIV as the virus enters the brain shortly after infection, leading to inflammation and BBB disruption ^[102][103][146,147]. In vitro studies have demonstrated that cultured brain pericytes can be infected by HIV, resulting in enhanced production of inflammatory mediators and disruption of endothelial barrier properties ^[104][105][148,149]. Furthermore, evidence from in vivo studies, including HIV patients and mouse models of HIV, has shown that brain pericytes can be infected by HIV ^{[106][107][108]}[150,151,152]. Following HIV infection, a reduction in pericyte coverage has been observed in the brains of HIV patients ^{[106][109][110]}[150,153,154]. Similar pericyte loss has also been detected in the brains of mouse models of HIV and SIV-infected macaques ^[109][110][153,154]. It has been suggested that the higher concentration of PDGF-BB induced by HIV Tat via the activation of mitogen-activated protein kinases and nuclear factor-κB pathways may drive HIV-induced pericyte loss in the brain ^[109][111][153,155]. However, the role of pericytes in HIV has not been extensively examined. A better understanding of pericyte dysfunction and loss in the context of HIV may provide opportunities for the development of novel therapeutics.

COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and affects various organs, including the heart, brain, and lungs ^{[112][113][114][115]}[156,157,158,159]. Cardiac pericytes, which express high levels of angiotensin-converting enzyme 2 (ACE-2), the main receptor for SARS-CoV-2, are major targets for viral infection ^{[116][117][118]}[160,161,162]. The infection of pericytes via SARS-CoV-2 contributes to cardiac complications associated with COVID-19, such as thrombosis, inflammation, and hemodynamic disturbances ^[119][163]. Studies have shown a significant loss of pericyte coverage in the heart capillaries of hamsters infected with SARS-CoV-2 ^[120][164]. Additionally, SARS-CoV-2 can infect cardiac pericytes, and its spike protein may induce pericyte dysfunction via CD147 receptor-mediated signaling pathway, leading to microvascular injury ^[113][157]. Brain pericytes, which also express ACE-2, are susceptible to SARS-CoV-2 infection, potentially driving inflammation and vascular dysfunction ^{[114][121][122]}[158,165,166]. Patients with COVID-19 have shown lower levels of the pericyte marker PDGFRβ in their cerebrospinal fluid ^[114][158]. SARS-CoV-2 spike protein has been found to deregulate vascular and immune functions in brain pericytes ^[123][167], while the SARS-CoV-2 envelope protein has been shown to induce brain pericyte death in vitro ^[124][168]. In the lung, pericytes were infected by SARS-CoV-2 and are detached from pulmonary capillary endothelium in COVID-19 patients ^[115][125][159,169]. However, the underlying mechanisms of pericyte loss in COVID-19 remain largely unknown, and further studies are needed to investigate the role of pericytes, particularly in long COVID-19 ^[126][170].

Overall, the loss of pericytes in infectious diseases can have significant negative effects on patient outcomes. Understanding the mechanisms underlying pericyte loss in these diseases is crucial for the development of new treatments that can prevent or reverse this process and improve patient outcomes. Further research is needed to gain a better understanding of the role of pericytes in infectious diseases and to explore novel therapeutic approaches that can target these cells.

Stroke, a leading cause of death and disability worldwide, is associated with pericyte dysfunction and BBB disruption ^[127][171]. Pericytes play a critical role in regulating inflammation, angiogenesis and BBB function during stroke ^[127][128][171,172]. A rapid reduction in brain pericyte number and coverage has been observed in human stroke cases as well as in experimental stroke models, including mice and rats, following ischemic damage ^{[74][129][130][131][132]}[113,173,174,175,176]. Pericyte apoptosis and autophagy have been detected in the brain from murine models of stroke, which may contribute to pericyte loss and BBB disruption ^[130][131][174,175]. The loss of regulator of G protein signaling 5 (RGS5) has been associated with increased pericyte number and improved BBB function in a mouse model of stroke, suggesting a role for RGS5 in brain pericyte loss during stroke ^[133][177]. Additionally, the inhibition of Sema3E/PlexinD1 signaling has been shown to increase pericyte number and enhance blood–brain barrier integrity in aged rats with stroke, further implicating this signaling pathway in brain pericyte loss ^[132][176]. Moreover, the deletion of hypoxia-inducible factors (HIF)-1 in pericytes has been found to prevent brain pericyte apoptosis and reduce vascular permeability in mice with stroke, indicating the involvement of pericyte HIF-1 in stroke-induced pericyte apoptosis ^[131][175]. In addition to maintaining BBB function by themselves, pericytes also promote the physiological functions of other BBB components including endothelial cells, basal lamina, and astrocytes ^[134][178]. For example, pericytes regulate aquaporin-4 polarization in mouse cortical astrocytes ^[135][179]. Furthermore, angiopoietin-1 secreted by pericytes mediates tight junction induction via the activation of Tie-2, an angiopoietin-1 receptor on EC ^{[134][136][137]}[178,180,181]. Therefore, restoration of pericyte coverage may improve BBB support and promote reperfusion after stroke ^[138][182]. Gaining more insights into the role of pericytes in stroke could facilitate the development of novel therapeutic approaches for stroke treatment ^[128][172].

TBI, caused by an external force, is the major cause of mortality and disability, particularly in young individuals ^[139][183]. The secondary injury following TBI involves oxidative stress, inflammation, and the production of matrix metalloproteinases (MMPs), which contribute to BBB dysfunction ^{[140][141][142]}[184,185,186]. Recent studies have highlighted pericyte degeneration as a significant factor in TBI, leading to regional microcirculatory hypoperfusion and increased BBB permeability ^[143][144][187,188]. A decline in pericyte markers has been observed in brain specimens from human TBI cases and in a mouse model of repetitive mild TBI up to 12 months post-injury ^[145][189]. Additionally, rapid pericyte loss in the acute phase of TBI has been documented in the brains of mice with TBI ^{[144][145][146][147][148]}[188,189,190,191,192]. Brain pericyte apoptosis has been detected in a mouse model of TBI, suggesting that pericyte loss during TBI may be attributed to apoptosis ^[149][193]. It has been found that the inhibition of the TNF-α/NF-κB/iNOS axis can reverse pericyte loss, improve pericyte function, and enhance microcirculation perfusion after TBI ^[144][188]. This indicates the potential contribution of the TNF-α/NF-κB/iNOS axis to pericyte loss in TBI. Consequently, the development of treatments that can prevent or reverse pericyte degeneration holds promise for the management of TBI and the secondary injuries that follow.

Overall, understanding the mechanisms of pericyte loss in these conditions is crucial for developing new treatments that can prevent or reverse this process and improve patient outcomes.