Table 1 Characterization of the mode of programmed endothelial cell death.

Apoptosis

Regulatory receptor

Exogenous: death-receptor ligand (Fas-associated death structural domain)/dependent receptor ligand

Nucleus: chromatin condensed and broken, nucleus consolidated, autophagosomes formed;

Cytosol: cellular integrity, crumpling, cytoplasmic efflux, and vacuolization of the cytosol membrane.

LPS-IL-6, PD-L1-HIF-α, NLRX1-TNF-α;

Promotes IκB degradation, NF-κB nuclear translocation, YAP phosphorylation, and activates apoptotic gene expression.

[15, 18, 25, 28, 33, 34]

Endogenous: Cyc release from mitochondrial damage, oxidative stress, etc.

Effector genes and proteins

Common apoptosis-related genes: Bax, Bcl-2, Bcl-xL, p53, etc.

Executioner caspases: caspase-3/6/7

Initiator Caspases: caspase-8/9/10

Mitochondria-cleave: Cyt-c, SMAC, mtDNA, etc.

Main process

Apoptotic vesicle formation;

Initiation of protein substrate hydrolysis;

DNA and key regulatory protein fragmentation.

Effect

Altered vascular permeability;

Inflammatory factor release;

Impairment of organ function.

Necroptosis

Regulatory receptor

RIPK1/3

Nucleus: chromatin breaks, DNA fragmentation

Cell membrane: rupture of the cell membrane, discharge of cytoplasmic contents leading to inflammation and other reactions

Necrotic apoptosis occurs in response to TNF, Fas, or TRAIL, among others, and has a highly proinflammatory effect

[37, 46,47,48]

Effector proteins

MIKL

Main process

RIPK1/3 activation, phosphorylation of MIKL, necrotic apoptotic cell membrane rupture, and content release

Effect

Altered vascular permeability; the

Inflammatory and cytokine storms;

Coagulation abnormalities;

Organ function impairment

Pyroptosis

Regulatory receptor

Classical pyroptosis pathway: NLRP3 captures ASC cleavage of GSDMD-N; activation of caspase-1 by LPS-HMGB1, NLRP-1/3, NLRC4

Nucleus: chromatin breaks, DNA fragmentation;

Cell membrane: formation of membrane pores, swelling and rupture of the cell, discharge of cytoplasmic contents, triggering inflammatory reactions.

Pyroptosis is a natural immune response triggered by the activation of inflammatory vesicle assembly, which promotes the mature secretion of inflammatory factors such as IL-1β and exacerbates the local inflammatory response

[23, 42,43,44,45]

Non-classical pyroptosis pathway: caspase-11 (murine origin), caspase-4/5 (human origin)

Effector proteins

Classical pathway: GSDMD-N integration to form membrane pores; casepase-1/3/9

Non-classical pathway: caspse-11, caspase-4/5 (human source)

Main process

Inflammatory vesicle NLRP3-ASC-GSDMD-N assembly activation, membrane pore formation, proinflammatory cytokine maturation, and release

Effect

Altered vascular permeability.

Inflammatory response;

Cytokine storm;

Coagulation abnormalities;

Organ function impairment

Ferroptosis

Regulatory receptor

GPX4 over depletion, NCOA4 autophagy-dependent iron death

Nucleus: no change

Cell membrane: ruptured

Mitochondria: outer mitochondrial membrane ruptured and crumpled; mitochondria darkly colored

Activation of JAK-STAT, NF-κB, inflammatory vesicles, cGAS-STING, and MAPK signaling pathways can lead to iron death

[37, 51,52,53]

Effector genes and proteins

Ferritin degradation; TFRC/HSPβ1-TFR-1; Nfr2-ROS; NCOA4 activation of the ATG5-ATG7-NCOA4 autophagy pathway, culminating in ferric iron overload

Main process

Iron ion-dependent lipid peroxide accumulation, iron overload, and (GPX4) downregulation

Effect

Altered vascular permeability;

Inflammatory response;

Impairment of organ function

PANoptosis

Molecular mechanisms

PANoptotic vesicles are downstream molecular initiation switches.

Currently, the more explicit PANoptotic upstream molecules include ZBP1, AIM2, RIPK1, etc. The known pathways are: S100a8/a9-Nrf1-PANoptosis; (CIRP)-ZBP1-PANoptosis; EIF2AK2-AIM2-PANoptosis, and the specific pathways need to be clarified.

-

NLRP12 drives inflammatory vesicle and PANoptosome activation through IRF1 and TLR2/4 in response to PAMP and TNF, causing cell death and promoting inflammation.

[21, 60,61,62,63,64]

[68, 69]